Substituted pyridyl amide compounds as modulators of the histamine h3 receptor

ABSTRACT

Certain substituted pyridyl amide compounds are histamine H 3  receptor modulators useful in the treatment of histamine H 3  receptor-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/803,407 filed on May 30, 2006 and of U.S. Provisional Application60/823,108 filed on Aug. 22, 2006, each of which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain pyridyl amide compounds,methods of making them, pharmaceutical compositions containing them, andmethods of using them for the treatment of disease states, disorders,and conditions mediated by the histamine H₃ receptor.

BACKGROUND OF THE INVENTION

The histamine H₃ receptor was first described as a presynapticautoreceptor in the central nervous system (CNS) (Arrang, J.-M. et al.,Nature 1983, 302, 832-837) controlling the synthesis and release ofhistamine. The histamine H₃ receptor is primarily expressed in themammalian central nervous system (CNS), with some minimal expression inperipheral tissues such as vascular smooth muscle.

Thus, several indications for histamine H₃ antagonists and inverseagonists have been proposed based on animal pharmacology and otherexperiments with known histamine H₃ antagonists (e.g. thioperamide).(See: “The Histamine H₃ Receptor—A Target for New Drugs”, Leurs, R. andTimmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000,408, 860-864.) These include conditions such as cognitive disorders,sleep disorders, psychiatric disorders, and other disorders.

For example, histamine H₃ antagonists have been shown to havepharmacological activity relevant to several key symptoms of depression,including sleep disorders (e.g. sleep disturbances, fatigue, andlethargy) and cognitive difficulties (e.g. memory and concentrationimpairment), as described above. For reviews, see: Celanire, S. DrugDiscovery Today 2005, 10(23/24), 1613-1627; Hancock, A. A. Biochem.Pharmacol. 2006, 71, 1103-1113.

Substituted diazepanyl benzamides were described as histamine H₃receptor antagonists in Intl. Patent Appl. Publ. WO05/040144 (May 6,2005). Substituted pyridines with antiangiogenic properties aredisclosed in U.S. Patent Appl. Publ. 2004/0014744 (Jan. 22, 2004).Substituted piperazines and diazepanes are described as histamine H₃receptor modulators in Intl. Patent Appl. Publ. WO03/004480 (Jan. 16,2003). However, there remains a need for potent histamine H₃ receptormodulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain pyridyl amide derivatives have now been found to have histamineH₃ receptor modulating activity. Thus, the invention is directed to thegeneral and preferred embodiments defined, respectively, by theindependent and dependent claims appended hereto, which are incorporatedby reference herein.

In one general aspect the invention relates to a compound of thefollowing Formula (I):

wherein

-   R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl;-   m is 1 or 2;-   X is N or CH;-   Y is N or CR^(a);    -   R^(a) is —H, —Z—Ar, —CH₂NR^(b)R^(c), —CN, —CO₂C₁₋₄alkyl, —CO₂H,        or —CONR^(b)R^(c);        -   where R^(b) and R^(c) are each independently —H or            —C₁₋₄alkyl; and

R² is —H or —Z—Ar;

-   with the proviso that one of X and Y is N and one of R^(a) and R² is    —Z—Ar; where Z is O or S; and    -   Ar is a phenyl or monocyclic heteroaryl group unsubstituted or        substituted with one, two, or three R³ substituents;        -   where each R³ substituent is independently selected from the            group consisting of: halo, —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl,            —SC₁₋₄alkyl, —CN, —CONR^(d)R^(e), and —NO₂;            -   where R^(d) and R^(e) are each independently —H or                —C₁₋₄alkyl;                or a pharmaceutically acceptable salt, a                pharmaceutically acceptable prodrug, or a                pharmaceutically active metabolite thereof.

In certain embodiments, the invention provides compounds of Formula(II):

wherein

-   R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl;-   each R³ substituent is independently selected from the group    consisting of: halo, —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —CN,    —CONR^(d)R^(e), and —NO₂;    -   where R^(d) and R^(e) are each independently —H or —C₁₋₄alkyl;        and-   n is 0, 1, 2, or 3;    or a pharmaceutically acceptable salt, a pharmaceutically acceptable    prodrug, or a pharmaceutically active metabolite thereof.

In certain embodiments, the invention provides compounds of Formula(III):

wherein

-   R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl;-   each R³ substituent is independently selected from the group    consisting of: halo, —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —CN,    —CONR^(d)R^(e), and —NO₂;    -   where R^(d) and R^(e) are each independently —H or —C₁₋₄alkyl;        and-   n is 0, 1, 2, or 3;    or a pharmaceutically acceptable salt, a pharmaceutically acceptable    prodrug, or a pharmaceutically active metabolite thereof.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically active metabolite thereof; and(b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by histamine H₃ receptor activity,comprising administering to the subject in need of such treatment aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof.

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is selected from: cognitive disorders,sleep disorders, psychiatric disorders, and other disorders.

In another general aspect, the invention is directed to methods ofmaking compounds of Formula (I) or Formula (II) or pharmaceuticallyacceptable salts thereof.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by /), ethyl(Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu),pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that inlight of the ordinary skill in the art and the teachings provided hereinwould be considered equivalent to any one of the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to embrace hydrates,solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotropically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the moiety for the variable appearingelsewhere. In other words, where a variable appears more than once, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula.

In preferred embodiments of Formula (I), R¹ is methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, or tert-butyl. In other preferredembodiments, R¹ is methyl or isopropyl. In still other preferredembodiments, R¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In preferred embodiments, m is 1. In other preferred embodiments, m is2.

In preferred embodiments, X is N, Y is CR^(a), and R² is —Z—Ar. In otherpreferred embodiments, X is CH, Y is N, and R² is —Z—Ar. In still otherpreferred embodiments, X is N, Y is CR^(a), and R² is —H, where R^(a) is—Z—Ar.

In preferred embodiments, R^(a) is —CN, —CONH₂, or —CH₂NH₂. In otherpreferred embodiments, R^(a) is —H.

In preferred embodiments, Z is O. In other preferred embodiments, Z isS.

In preferred embodiments, Ar is a phenyl, pyrrolyl, furanyl, thiophenyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, or pyrazinyl group, each unsubstituted or substituted withone, two, or three R³ substituents. In other preferred embodiments, Aris a phenyl group unsubstituted or substituted with one, two, or threeR³ substituents. In still other preferred embodiments, Ar is a4-halophenyl group. In further preferred embodiments, Ar is phenyl,3,4-dichlorophenyl, 4-methylsulfanylphenyl, 3-chlorophenyl,3-fluorophenyl, 4-chloro-3-methylphenyl, 3-cyanophenyl, 4-chlorophenyl,4-fluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 3-chlorophenyl,2,4-difluorophenyl, 3,5-dichlorophenyl, 2,5-difluorophenyl,3,5-difluorophenyl, 3-methyl-4-methylsulfanylphenyl, or 3-pyridyl.

In preferred embodiments of Formula (II) and Formula (III), R¹ iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In certain preferred embodiments, the compound of Formula (I) isselected from the group consisting of:

Ex. Chemical Name 1[6-(3,4-Dichloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 2(4-Isopropyl-piperazin-1-yl)-[6-(pyridin-3-yloxy)-pyridin-3-yl]-methanone;3(4-Isopropyl-piperazin-1-yl)-[6-(4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 4[6-(3-Chloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 5(4-Isopropyl-piperazin-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone; 6[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 73-[5-(4-Isopropyl-piperazine-1-carbonyl)-pyridin-2-yloxy]-benzonitrile;8 [6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 9(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone; 10[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone; 113-[5-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitrile; 12[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone; 13(4-Cyclopropyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone;14(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone; 15[6-(3,4-Dichloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 16[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 17[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 18(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 19(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 203-[5-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitrile; 21(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone; 22(4-Cyclopropyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 23[6-(3-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone; 24[6-(3-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 25[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 26(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-difluoro-phenoxy)-pyridin-3-yl]-methanone; 27(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-difluoro-phenoxy)-pyridin-3-yl]-methanone; 28[6-(3,4-Difluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 29(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(2-fluoro-phenoxy)-pyridin-3-yl]-methanone; 30(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(2,4-difluoro-phenoxy)-pyridin-3-yl]-methanone; 31(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2-fluoro-phenoxy)-pyridin-3-yl]-methanone; 32(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2,4-difluoro-phenoxy)-pyridin-3-yl]-methanone; 33(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,5-dichloro-phenoxy)-pyridin-3-yl]-methanone; 34(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2,5-difluoro-phenoxy)-pyridin-3-yl]-methanone; 35(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,5-dichloro-phenoxy)-pyridin-3-yl]-methanone; 36(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,5-difluoro-phenoxy)-pyridin-3-yl]-methanone; 37(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3-fluoro-phenoxy)-pyridin-3-yl]-methanone; 38[6-(3-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 39(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3-fluoro-phenoxy)-pyridin-3-yl]-methanone; 40(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 41(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 42(4-Isopropyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 43[6-(3,4-Dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 44(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone; 45(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone; 46[6-(3,4-Dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 47[6-(4-Chloro-3-methyl-phenoxy)-pyridin-2-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone; 48[6-(4-Chloro-3-methyl-phenoxy)-pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 49[6-(4-Chloro-3-methyl-phenoxy)-pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 50[5-(3,4-Dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone; 51(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone; 52(4-Cyclopropyl-[1,4]diazepan-1-yl)-[5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone; 533-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile; 543-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carboxylic acid amide; 556-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile; 566-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(pyridin-3-yloxy)-pyridine-2-carbonitrile; 573-(4-Chloro-3-methyl-phenoxy)-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile; 586-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(3,4-dichloro-phenoxy)-pyridine-2-carbonitrile; 596-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-fluoro-phenoxy)-pyridine-2-carbonitrile; 606-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(3-fluoro-phenoxy)-pyridine-2-carbonitrile; 616-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(2-fluoro-phenoxy)-pyridine-2-carbonitrile; 626-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carboxylic acid amide; 636-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(pyridin-3-yloxy)-pyridine-2-carboxylic acid amide; 64[6-Aminomethyl-5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 65(4-Cyclopentyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone;66(4-Cyclopentyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone; 67(4-Cyclopentyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 68[5-(4-Chloro-phenoxy)-pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 69(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(4-fluoro-phenoxy)-pyridin-2-yl]-methanone; 70[5-(3-Chloro-phenoxy)-pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 71(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(3-fluoro-phenoxy)-pyridin-2-yl]-methanone; 72(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(2-fluoro-phenoxy)-pyridin-2-yl]-methanone; 73[6-(2-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 74(4-Cyclopentyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 75[6-(2-Chloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 76[6-(2-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 77[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 78(4-Cyclopentyl-piperazin-1-yl)-[6-(2-fluoro-phenoxy)-pyridin-3-yl]-methanone; 79(4-Cyclobutyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 80[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone; 816-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-phenoxy-pyridine-2-carbonitrile; 826-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-3-(4-fluoro-phenoxy)-pyridine-2-carbonitrile; 83(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenylsulfanyl)-pyridin-3-yl]-methanone; 84(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(4-fluoro-phenylsulfanyl)-pyridin-2-yl]-methanone; 85[6-(4-Chloro-phenylsulfanyl)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 86(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenylsulfanyl-pyridin-3-yl)-methanone; 87(4-Cyclopentyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 88(4-Isopropyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 89[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 90(4-Ethyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 91(4-Cyclobutyl-[1,4]diazepan-1-yl)-(5-phenylsulfanyl-pyridin-2-yl)-methanone; 92[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone; 93[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isobutyl-piperazin-1-yl)-methanone; 94(4-Cyclobutyl-[1,4]diazepan-1-yl)-(5-phenylsulfanyl-pyridin-2-yl)-methanone; 95(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenylsulfanyl-pyridin-3-yl)-methanone; 96[6-(4-Chloro-phenylsulfanyl)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone; 97(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenylsulfanyl)-pyridin-3-yl]-methanone; 98(4-Ethyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone; 99[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone; 100(4-Cyclopentyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 101(4-Isopropyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone; 102(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-o-tolyloxy-pyridin-3-yl)-methanone;103(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-m-tolyloxy-pyridin-3-yl)-methanone;104(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-p-tolyloxy-pyridin-3-yl)-methanone;and 105(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone;and pharmaceutically acceptable salts thereof.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I), preferably of those described above and of thespecific compounds exemplified herein, and methods of treatment usingsuch salts. In a preferred embodiment, the invention refers tohydrochloride monohydrates of compounds of Formula (I).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as benzylamines, pyrrolidines, piperidine,morpholine, and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I), which may also be used inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997,40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of thehistamine H₃ receptor in the methods of the invention. As suchmodulators, the compounds may act as antagonists, agonists, or inverseagonists. The compounds of the invention may be used in the methods forthe treatment or prevention of medical conditions, diseases, ordisorders mediated through modulation of the histamine H₃ receptor, suchas those described herein.

The term “treat” or “treating” as used herein is intended to refer toadministration of a compound or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of histamine H₃ receptor activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of histamine H₃ receptor activity.The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate histamine H₃ receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate histamine H₃ receptorexpression or activity.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by histamine H₃ receptoractivity, such as: cognitive disorders, sleep disorders, psychiatricdisorders, and other disorders. Symptoms or disease states are intendedto be included within the scope of “medical conditions, disorders, ordiseases.”

Cognitive disorders include, for example, dementia, Alzheimer's disease(Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21, 1977), cognitivedysfunction, mild cognitive impairment (pre-dementia), attention deficithyperactivity disorders (ADHD), attention-deficit disorders, andlearning and memory disorders (Barnes, J. C. et al., Soc. Neurosci.Abstr. 1993, 19, 1813). Learning and memory disorders include, forexample, learning impairment, memory impairment, age-related cognitivedecline, and memory loss. H₃ antagonists have been shown to improvememory in a variety of memory tests, including the elevated plus maze inmice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), atwo-trial place recognition task (Orsetti, M. et al. Behav. Brain Res.2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S.et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and theradial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10),905-910). Also, in the spontaneously hypertensive rat, an animal modelfor the learning impairments in attention-deficit disorders, H₃antagonists were shown to improve memory (Fox, G. B. et al. Behav. BrainRes. 2002, 131(1-2), 151-161).

Sleep disorders include, for example, insomnia, disturbed sleep,narcolepsy (with or without associated cataplexy), cataplexy, disordersof sleep/wake homeostasis, idiopathic somnolence, excessive daytimesleepiness (EDS), circadian rhythm disorders, fatigue, lethargy, jetlag, and REM-behavioral disorder. Fatigue and/or sleep impairment may becaused by or associated with various sources, such as, for example,sleep apnea, perimenopausal hormonal shifts, Parkinson's disease,multiple sclerosis (MS), depression, chemotherapy, or shift workschedules.

Psychiatric disorders include, for example, schizophrenia (Schlicker, E.and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353,290-294), bipolar disorders, manic disorders, depression (Lamberti, C.et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. etal. Psychopharmacology 1999, 142(2), 215-220) (Also see: Stark, H. etal., Drugs Future 1996, 21(5), 507-520; and Leurs, R. et al., Prog. DrugRes. 1995, 45, 107-165 and references cited therein.),obsessive-compulsive disorder, and post-traumatic stress disorder.

Other disorders include, for example, motion sickness, vertigo (e.g.vertigo or benign postural vertigo), tinitus, epilepsy (Yokoyama, H. etal., Eur. J. Pharmacol. 1993, 234, 129-133), migraine, neurogenicinflammation, eating disorders (Machidori, H. et al., Brain Res. 1992,590, 180-186), obesity, substance abuse disorders, movement disorders(e.g. restless leg syndrome), and eye-related disorders (e.g. maculardegeneration and retinitis pigmentosis).

Particularly, as modulators of the histamine H₃ receptor, the compoundsof the present invention are useful in the treatment or prevention ofdepression, disturbed sleep, narcolepsy, fatigue, lethargy, cognitiveimpairment, memory impairment, memory loss, learning impairment,attention-deficit disorders, and eating disorders.

In treatment methods according to the invention, an effective amount ofat least one compound according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition.

Effective amounts or doses of the compounds of the present invention maybe ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the compound, the severity and course of thedisease, disorder, or condition, the subject's previous or ongoingtherapy, the subject's health status and response to drugs, and thejudgment of the treating physician. An example of a dose is in the rangeof from about 0.001 to about 200 mg of compound per kg of subject's bodyweight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combinationwith additional active ingredients in the treatment of the aboveconditions. In an exemplary embodiment, additional active ingredientsare those that are known or discovered to be effective in the treatmentof conditions, disorders, or diseases mediated by histamine H₃ receptoractivity or that are active against another target associated with theparticular condition, disorder, or disease, such as H₁ receptorantagonists, H₂ receptor antagonists, H₃ receptor antagonists,topiramate (Topamax™), and neurotransmitter modulators such asserotonin-norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors,non-selective serotonin re-uptake inhibitors (NSSRIs),acetylcholinesterase inhibitors (such as tetrahydroaminoacridine,Donepezil (Aricept™), Rivastigmine, or Galantamine (Reminyl™)), ormodafinil. The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of a compound according to the invention), decrease one ormore side effects, or decrease the required dose of the compoundaccording to the invention.

More particularly, compounds of the invention in combination withmodafinil are useful for the treatment of narcolepsy, excessive daytimesleepiness (EDS), Alzheimer's disease, depression, attention-deficitdisorders, MS-related fatigue, post-anesthesia grogginess, cognitiveimpairment, schizophrenia, spasticity associated with cerebral palsy,age-related memory decline, idiopathic somnolence, or jet-lag.Preferably, the combination method employs doses of modafinil in therange of about 20 to 300 mg per dose.

In another embodiment, compounds of the invention in combination withtopiramate are useful for the treatment of obesity. Preferably, thecombination method employs doses of topiramate in the range of about 20to 400 mg per dose.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a compound of the invention andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the compounds of the invention may be prepared usingsuitable pharmaceutical excipients and compounding techniques now orlater known or available to those skilled in the art. The compositionsmay be administered in the inventive methods by oral, parenteral,rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil, sesame oil, or olive oil, liquid paraffin, amixture of mono and di-glycerides of short chain fatty acids,polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid compositions may optionally contain: pharmaceutically-acceptableexcipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel and the like); non-aqueousvehicles, e.g., oil (for example, almond oil or fractionated coconutoil), propylene glycol, ethyl alcohol, or water; preservatives (forexample, methyl or propyl p-hydroxybenzoate or sorbic acid); wettingagents such as lecithin; and, if desired, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.

Referring to Scheme A, 3-bromo-pyridines (3), where Hal is bromo,chloro, or fluoro, are commercially available or prepared using methodsknown to one skilled in the art. Displacement of the Hal substituent isaccomplished by reaction with Ar—ZH reagents, in the presence of asuitable base such as K₂CO₃, Na₂CO₃, Cs₂CO₃, NaH, or a mixture thereof,in a polar solvent such as N,N-dimethylformamide (DMF), ethylene glycoldimethyl ether (DME), N,N-dimethylacetamide (DMA), dimethylsulfoxide(DMSO), or a mixture thereof, at a temperature between room temperatureand the reflux temperature of the solvent, or subject to microwaveirradiation, to provide ethers and thioethers (4). Transitionmetal-catalyzed reaction of bromides (4) with amines (5) and a COequivalent, such as CO gas or Mo(CO)₆, in the presence of a suitablepalladium (II) catalyst, and optional additives such as t-BuPHBF₄ ⁺,provide compounds of Formula (I) where Y is N and R² is —Z—Ar.Alternatively, halogen-metal exchange of the bromine atom of (4) bytreatment with n-BuLi or t-BuLi and quenching with a CO₂ equivalentprovides the corresponding carboxylic acids. Amide coupling of suchacids with amines (5), in the presence of coupling agents known to oneskilled in the art, also provides compounds of Formula (I) where Y is Nand R² is —Z—Ar.

Amide coupling of pyridine carboxylic acids (6) (where A is OH) (6) withamines (5) provides amides (7). Alternatively, acid chlorides (6) (whereA is Cl) may be reacted with amines (5) in the presence of a suitablebase such as Et₃N, iPr₂NEt, pyridine, or a mixture thereof to formamides (7). One skilled in the art will recognize that R¹ may bereplaced by a suitable amine protecting group and then introduced at alater point in the synthesis. Displacement of the Hal group as describedin Scheme A provides compounds of Formula (I) where Y is N and R² is—Z—Ar.

A method of making a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, is shown in Scheme B-1. A method of making acompound of Formula (II), or a pharmaceutically acceptable salt thereof,comprises reacting a compound of formula (7-1) with a compound offormula B3 in the presence of at least one equivalent of a first base,such as NaOH, KOH, K₂CO₃ or Cs₂CO₃, in a first organic solvent such asDMF, DMA, DME, DMSO, or acetonitrile, or a mixture thereof, to give acompound of Formula (II). In preferred embodiments, the reaction isheated at a temperature of about 100° C. In a further preferredembodiment, the compound of formula (7-1) is(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone, thecompound of formula B3 is 4-fluorophenol, the first base is Cs₂CO₃(preferably at least 1.5 equivalents, and more preferably about 2equivalents), the first organic solvent is DMA (preferably, about0.5-0.75 M solution), and the compound of Formula (II) is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone.

The method of making a compound of Formula (II) further comprisesreacting a compound of formula (5-1) with 6-chloronicotinyl chloride inthe presence of a second base, such as aq. NaOH, aq. KOH, Et₃N, oriPr₂NEt, in a second organic solvent such as DCM, dichloroethane (DCE),toluene, or isopropyl acetate, to give a compound of formula (7-1). In afurther preferred embodiment, the compound of formula (5-1) is1-cyclobutyl-[1,4]diazepane dihydrochloride, the second base is 1 Naqueous NaOH, the second organic solvent is isopropyl acetate, and thecompound of formula (7-1) is(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)methanone.

The method of making a compound of Formula (II) further comprisesreacting a compound of formula B2 with a suitable acid, such as TFA orHCl, in a third organic solvent such as DCM, dioxane, or MeOH, or amixture thereof, to give an amine salt of formula (5-1). In a furtherpreferred embodiment, the compound of formula B2 is4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester, the acidis HCl, the third organic solvent is dioxane, and the compound offormula (5-1) is 1-cyclobutyl-[1,4]diazepane dihydrochloride.

The method of making a compound of Formula (II) further comprisesreacting tert-butylhomopiperazine-1-carboxylate (preferably, about0.9-1.1 molar equivalents) via reductive amination with an aldehyde orketone of formula R¹═O (preferably, about 0.9-1.1 molar equivalents) inthe presence of at least one molar equivalent of a reducing agent, suchas NaB(OAc)₃H or NaCNBH₃, in a fourth organic solvent such as DCE, THF,EtOAc, ethanol, or methanol, to give a compound of formula B2. In afurther preferred embodiment, R¹═O is cyclobutanone, the reducing agentis NaB(OAc)₃H (preferably, at least 1.1 molar equivalents), the fourthorganic solvent is dichloroethane (preferably, about 0.2 M-0.5 Msolution), and the compound of formula B2 is4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester.

In a preferred embodiment, a compound of Formula (II) is reacted withHCl (preferably, about 0.95 equivalents) in a fifth organic solvent suchas ethanol, methanol, isopropanol, EtOAc, or an ethanol/Et₂O mixture, toprovide a pharmaceutically acceptable salt of the compound of Formula(II). In a further preferred embodiment, the compound of Formula (II) is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone,the fifth organic solvent is ethanol/Et₂O (preferably, about 1:1mixture), and the pharmaceutically acceptable salt of Formula (II) is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate.

Referring to Scheme C, pyridines (8), where the Hal substituent is atthe 5- or 6-position of the pyridine are coupled with amines (5) usinggeneral amide coupling methods to give amides (9). Replacement of theHal substituent with —Z—Ar is accomplished by: 1) displacement by Ar—ZHreagents under basic conditions as described in Scheme A; or 2) Ullmanncoupling in the presence of a suitable copper (I) catalyst, such as CuI,in a solvent such as DMF, DMSO, hexamethylphosphoramide (HMPA), or amixture thereof, to provide compounds of Formula (I) where Y is CR^(a),R^(a) is —Z—Ar, and R² is —H or compounds of Formula (I) where Y is CHand R² is —Z—Ar.

Compounds of Formula (I) where X is N, Y is CR^(a), R^(a) is —CN, and R²is —Z—Ar may be prepared from cyano amides (15), which are accessed asshown in Scheme D. Pyridine-2-carboxylic acids (10) are converted to theN-oxide analogs (12) by reaction with urea-hydrogen peroxide complex andtrifluoroacetic acid anhydride. Installation of the cyano substituent isaccomplished by reaction with trimethylsilyl cyanide (TMSCN) anddimethylcarbamyl chloride to provide nitrile acids (13). Alternatively,acids (10) may be esterified according to known methods to give esters(11), which may be converted to N-oxide esters (12). Following reactionwith TMSCN and dimethylcarbamyl chloride to install the cyano group,hydrolysis of the ester group provides acids (13). Acids (13) areconverted to cyano amides (15) by amide coupling with amines (5) asdescribed in Scheme A. Alternatively, N-oxides (12), where R is H, maybe coupled with amines (5) directly, using amide coupling methods asdescribed in Scheme A. N-oxide amides (14) are reacted with TMSCN anddimethylcarbamyl chloride to give the corresponding cyano amides (15).Reaction of amides (15) via displacement or Ullmann coupling protocolsas described in Schemes A and C provide compounds of Formula (I) where Xis N, Y is CR^(a), R^(a) is —CN, and R² is —Z—Ar. Nitriles (15) arereduced to the corresponding aminomethyl analogs or hydrolyzed to formamides (not shown).

A method of making a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, is also shown in Scheme E. A method of making acompound of Formula (II), or a pharmaceutically acceptable salt thereof,comprises reacting a compound of formula E3 (preferably, about 1equivalents) via reductive amination with a compound of formula R¹═O(preferably, at least 1 equivalent and more preferably, about 1.2equivalents) in the presence of a suitable reducing agent such asNaB(OAc)₃H or NaCNBH₃ (preferably, at least 1 equivalent and, morepreferably, about 1.5 equivalents), in a sixth organic solvent such asDCE, THF, EtOAc, ethanol, or methanol, at a temperature of about 0° C.to about 40° C., to give a compound of Formula (II). In a furtherpreferred embodiment, the compound of formula E3 is(1,4-diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone, R¹═O iscyclobutanone, the reducing agent is NaB(OAc)₃H, the sixth organicsolvent is EtOAc, and the compound of Formula (II) is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone.

The method of making a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, further comprises reacting a compound offormula E2 (preferably, about 1 equivalent) with homopiperazine(preferably, at least 1 equivalent and more preferably, about 2.4equivalents), in the presence of an organometallic reagent, such as analkyl Grignard reagent or alkyllithium reagent (preferably, at least 1equivalent and more preferably, about 1.5 equivalents), in an aproticorganic solvent, at a temperature between about 0° C. and about 30° C.,to give a compound of formula E3. Examples of suitable organometallicreagents include R^(y)MgBr, R^(y)MgCl, or R^(y)Li, where R^(y) ismethyl, ethyl, propyl, isopropyl, butyl, or hexyl. Suitable aproticorganic solvents include THF, Et₂O, MTBE, or 2-methyl-THF. In apreferred embodiment, the compound of formula E2 is ethyl6-(4-fluorophenoxy)nicotinate, the organometallic reagent ishexyllithium, the aprotic organic solvent is THF, and the compound offormula E3 is[1,4]diazepan-1-yl-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone.

The method of making a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, further comprises reacting a compound offormula E1, where R^(x) is methyl or ethyl (preferably, about 1equivalent), with a compound of formula B3 (preferably, about 1.1equivalents) in the presence of a base (such as Cs₂CO₃, K₂CO₃, NaOH, orKOH, or the like) (preferably, about 1.1 equivalents), in a polar,aprotic organic solvent, at a temperature between about room temperatureand about 80° C., to give a compound of formula E2. Suitable polar,aprotic organic solvents include DMF, DMA, DMSO, or acetonitrile. In afurther preferred embodiment, the compound of formula E1 is ethyl6-chloronicotinate, the compound of formula B3 is 4-fluorophenol, thebase is Cs₂CO₃, the polar, aprotic organic solvent is DMF, and thecompound of formula E2 is ethyl 6-(4-fluorophenoxy)nicotinate.

The method of making a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, further comprises: a) diluting a solution ofthe compound of Formula (II) in EtOAc with ethanol; and b) treating theresulting solution with concentrated aqueous HCl (0.95 equivalents) toprovide the hydrochloride salt of the compound of Formula (II).Preferably, the hydrochloride monohydrate of Formula (II) is formed.Preferably, the solution of the compound of Formula (II) in EtOAc isobtained from the reaction of a compound of formula E3 with a compoundof formula R¹═O. In a preferred embodiment, the compound of Formula (II)is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone.In a preferred embodiment, the pharmaceutically acceptable salt of acompound of Formula (II) is(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate.

Those skilled in the art will recognize that several of the chemicaltransformations described above may be performed in a different orderthan that depicted in the above Schemes.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, amines ofFormula (I) may be treated with trifluoroacetic acid (TFA), HCl, orcitric acid in a solvent such as diethyl ether (Et₂O), dichloromethane(DCM), tetrahydrofuran (THF), or methanol (MeOH) to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

EXAMPLES Chemistry

In preparing the compounds described in the examples below, thefollowing general experimental methods were employed unless otherwiseindicated.

Where solutions or mixtures were “concentrated”, they were concentratedunder reduced pressure using a rotary evaporator. Unless otherwisespecified, reaction solutions were stirred at room temperature (rt)under a N_(2(g)) atmosphere.

Normal phase flash column chromatography (FCC) was typically performedwith RediSep® silica gel columns using 2 M NH₃ in MeOH/DCM as eluent,unless otherwise indicated.

Preparative Reversed-Phase high performance liquid chromatography (HPLC)was typically performed using a Gilson® instrument with a YMC-PackODS-A, 5 μm, 75×30 mm column, a flow rate of 25 mL/min, detection at 220and 254 nm, with a 15% to 99% acetonitrile/(water/0.05% TFA) gradient(acidic conditions) or an acetonitrile/(water/20 mM NH₄OH) gradient(basic conditions).

Analytical Reversed-Phase HPLC (Method B) was performed using a HewlettPackard instrument with a Zorbax Eclipse XBD-C8, 5 mm, 4.6×150 mmcolumn, and a gradient of 1%-99% acetonitrile/water over 8.0 min.

Analytical Reversed-Phase HPLC (Method C) was performed using aHewlett-Packard HP1100 HPLC System equipped with a Zorbax EclipseXDB-C18; 4.6×50 mm, 1.8 μM column with a 2 mL/min flow rate anddetection at 220 and 250 nm. The mobile phase was Solvent A: 0.1%TFA/water; Solvent B: 0.1% TFA/Acetonitrile. The gradient run was: 0 min(A:B, 75:25); 1.0 min (A:B, 75:25); 2.0 min (A:B, 5:95).

Trifluoroacetic acid salts were obtained by purification of the crudereaction product by preparative reverse phase HPLC.

In obtaining the characterization data described in the examples below,the following analytical protocols were followed unless otherwiseindicated.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. Calculated mass corresponds to the exact mass.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz),DPX500 (500 MHz), DRX600 (600 MHz) spectrometer. The format of the ¹HNMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoftCorp., Cambridge, Mass.).

Example 1[6-(3,4-Dichloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

Step A; 5-Bromo-2-(3,4-dichloro-phenoxy)-pyridine

To a solution of 2,5-dibromopyridine (2.412 g, 10.18 mmol) in DMF (50mL) was added K₂CO₃ (5.22 g, 37.8 mmol) and 3,4-dichlorophenol (2.66 g,16.3 mmol). The mixture was heated at 90° C. for 18 h then allowed tocool to room temperature (rt). Water was added and the mixture wasextracted with DCM. Purification by FCC provided the desired product(3.23 g, 100%). ¹H NMR (400 MHz, CDCl₃): 8.21 (dd, J=2.5, 0.8 Hz, 1H),7.81 (dd, J=8.3, 3.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.26 (d, J=1.5 Hz,1H), 7.00 (dd, J=9.0, 2.5 Hz, 1H), 6.88 (dd, J=8.8, 0.8 Hz, 1H).

Step B

To a solution of 5-bromo-2-(3,4-dichloro-phenoxy)-pyridine (0.303 g,0.949 mmol) in THF (4 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU; 0.30 mL, 2.0 mmol), cyclopropyl piperazine (0.30 mL, 2.4 mmol),trans-di-m-acetatobis[2-(di-o-tolylphosphino)benzyl]di-palladium (II)(Hermann's catalyst; 36.7 mg, 0.039 mmol), t-BuPHBF₄ ⁺ (17.4 mg, 0.060mmol), and Mo(CO)₆ (301 mg, 1.14 mmol). The reaction mixture was heatedin the microwave for 6 min at 125° C., cooled to rt, then concentrated.Purification by FCC gave the desired product (284 mg, 76%). MS (ESI):mass calcd. for C₁₉H₂₁Cl₂N₃O₂, 393.10; m/z found, 394.7 [M+H]⁺. ¹H NMR(CDCl₃): 8.24 (dd, J=2.5, 0.8 Hz, 1H), 7.83 (dd, J=8.3, 2.5 Hz, 1H),7.47 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz,1H), 7.00 (dd, J=8.3, 0.8 Hz, 1H), 3.90-3.40 (br m, 4H), 2.74 (h, J=6.8Hz, 1H), 2.64-2.43 (br m, 4H), 1.04 (d, J=7.1 Hz, 6H).

The compounds in Examples 2-42 were prepared using procedures analogousto those outlined in Example 1.

Example 2(4-Isopropyl-piperazin-1-yl)-[6-(pyridin-3-yloxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₁₈H₂₂N₄O₂, 326.17; m/z found, 327.7 [M+H]⁺.¹H NMR (CDCl₃): 8.53 (d, J=2.7 Hz, 1H), 8.50 (dd, J=4.9, 1.1 Hz, 1H),8.23 (d, J=2.7 Hz, 1H), 7.85 (dd, J=8.2, 2.5 Hz, 1H), 7.56-7.53 (m, 1H),7.37 (dd, J=8.4, 2.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.90-3.36 (m, 4H),2.75 (h, J=6.8 Hz, 1H), 2.66-2.39 (m, 4H), 1.06 (d, J=6.0 Hz, 6H).

Example 3(4-Isopropyl-piperazin-1-yl)-[6-(4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₆N₃O₂S, 371.17; m/z found, 372.7 [M+H]⁺.¹H NMR (CDCl₃): 8.27 (d, J=2.5 Hz, 1H), 7.81 (dd, J=8.5, 2.2 Hz, 1H),7.33 (d, J=8.8 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 6.97 (d, J=8.1 Hz, 1H),3.87-3.41 (m, 4H), 2.75 (h, J=6.6 Hz, 1H), 2.63-2.42 (m, 7H), 1.06 (d,J=6.3 Hz, 6H).

Example 4[6-(3-Chloro-phenoxy)-Pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₂ClN₃O₂, 359.14; m/z found, 360.1 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.5, 2.7 Hz, 1H),7.34 (dd, J=8.0, 8.0 Hz, 1H), 7.23-7.20 (m, 1H), 7.18 (dd, J=2.2, 2.2Hz, 1H), 7.07-7.04 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 3.87-3.38 (m, 4H),2.74 (h, J=6.5 Hz, 1H), 2.65-2.41 (m, 4H), 1.05 (d, J=6.6 Hz, 6H).

Example 5(4-Isopropyl-piperazin-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₃N₃O₂, 325.18; m/z found, 326.7 [M+H]⁺.¹H NMR (CDCl₃): 8.27 (d, J=2.7 Hz, 1H), 7.81 (dd, J=8.5, 2.5 Hz, 1H),7.46-7.41 (m, 2H), 7.27-7.23 (m, 1H), 7.18-7.14 (m, 2H), 6.96 (d, J=8.5Hz, 1H), 3.86-3.40 (m, 4H), 2.75 (h, J=6.6 Hz, 1H), 2.66-2.41 (m, 4H),1.06 (d, J=6.3 Hz, 6H).

Example 6[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₄ClN₃O₂, 373.16; m/z found, 374.7 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (d, J=2.2 Hz, 1H), 7.82 (dd, J=8.8, 2.5 Hz, 1H),7.28 (d, J=8.5 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H),6.94 (dd, J=8.2, 2.7 Hz, 1H), 3.87-3.41 (m, 4H), 2.75 (h, J=6.3 Hz, 1H),2.65-2.43 (m, 4H), 1.06 (d, J=6.6 Hz, 6H).

Example 73-[5-(4-Isopropyl-piperazine-1-carbonyl)-pyridin-2-yloxy]-benzonitrile

MS (ESI): mass calcd. for C₂₀H₂₂N₄O₂, 350.17; m/z found, 351.7 [M+H]⁺.¹H NMR (CDCl₃): 8.24 (dd, J=2.2, 0.8 Hz, 1H), 7.87 (dd, J=8.2, 2.5 Hz,1H), 7.55-7.53 (m, 2H), 7.50-7.49 (m, 1H), 7.45-7.41 (m, 1H), 7.05 (dd,J=8.2, 0.5 Hz, 1H), 3.87-3.41 (m, 4H), 2.76 (h, J=6.9 Hz, 1H), 2.68-2.44(m, 4H), 1.06 (d, J=6.6 Hz, 6H).

Example 8[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₂ClN₃O₂, 359.14; m/z found, 360.7 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (dd, J=2.5, 1.1 Hz, 1H), 7.83 (dd, J=8.5, 2.5 Hz,1H), 7.41-7.37 (m, 2H), 7.13-7.09 (m, 2H), 6.99 (dd, J=8.8, 0.5 Hz, 1H),3.85-3.41 (m, 4H), 2.75 (h, J=6.3 Hz, 1H), 2.65-2.43 (m, 4H), 1.06 (d,J=6.6 Hz, 6H).

Example 9(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂N₃O₂, 405.10; m/z found, 406.7[M+H]⁺. ¹H NMR (CDCl₃): 8.22 (br s, 1H), 7.82-7.78 (m, 1H), 7.46 (d,J=8.8 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.02 (dd, J=8.8, 2.6 Hz, 1H),6.98 (br d, J=8.5 Hz, 1H), 3.77-3.71 (m, 1H), 3.52-3.44 (m, 3H),3.43-3.38 (m, 1H), 2.97-2.92 (m, 1H), 2.89-2.72 (m, 3H), 1.98-1.71 (m,3H), 0.52-0.33 (m, 4H).

Example 10[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₂ClN₃O₂, 371.14; m/z found, 372.4 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (d, J=2.2 Hz, 1H), 7.82-7.76 (m, 1H), 7.40-7.35 (m,2H), 7.12-7.07 (m, 2H), 6.96 (d, J=8.8 Hz, 1H), 3.78-3.71 (m, 2H),3.53-3.45 (m, 2H), 2.98-2.93 (m, 1H), 2.88-2.75 (m, 3H), 1.97-1.75 (m,3H), 0.52-0.34 (m, 4H).

Example 113-[5-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitrile

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂, 362.17; m/z found, 363.7 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (br s, 1H), 7.87-7.82 (m, 1H), 7.55-7.51 (m, 2H),7.50 (br s, 1H), 7.45-7.41 (m, 1H), 7.04 (d, J=8.5 Hz, 1H), 3.79-3.74(m, 2H), 3.55-3.49 (m, 2H), 3.00-2.95 (m, 1H), 2.89-2.78 (m, 3H),2.00-1.79 (m, 3H), 0.54-0.36 (m, 4H).

Example 12[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.25 (d, J=1.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.38(d, J=8.2 Hz, 1H), 7.04 (d, J=2.7 Hz, 1H), 6.99-6.92 (m, 2H), 3.78-3.72(m, 2H), 3.56-3.47 (m, 2H), 3.00-2.94 (m, 1H), 2.89-2.76 (m, 3H),1.99-1.76 (m, 3H), 0.53-0.35 (m, 4H).

Example 13(4-Cyclopropyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₃N₃O₂, 337.18; m/z found, 338.2 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (d, J=2.5 Hz, 1H), 7.82-7.76 (m, 1H), 7.46-7.41 (m,2H), 7.27-7.23 (m, 1H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.2 Hz, 1H),3.78-3.73 (m, 2H), 3.56-3.48 (m, 2H), 3.00-2.94 (m, 1H), 2.89-2.76 (m,3H), 1.99-1.76 (m, 3H), 0.53-0.35 (m, 4H).

Example 14(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₃Cl₂N₃O₂, 419.12; m/z found, 420.3[M+H]⁺. ¹H NMR (CDCl₃): 8.23 (br s, 1H), 7.82 (dd, J=8.3, 2.3 Hz, 1H),7.47 (d, J=8.8 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.03 (dd, J=8.6, 2.3 Hz,1H), 6.99 (d, J=8.6 Hz, 1H), 3.80-3.73 (m, 2H), 3.57-3.48 (m, 2H),2.96-2.81 (m, 1H), 2.65-2.59 (m, 1H), 2.53-2.41 (m, 3H), 2.10-1.91 (m,3H), 1.89-1.65 (m, 5H).

Example 15[6-(3,4-Dichloro-phenoxy)-Pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₃Cl₂N₃O₂, 407.12; m/z found, 408.2[M+H]⁺. ¹H NMR (CDCl₃): 8.24 (br s, 1H), 7.82 (dd, J=8.3, 2.5 Hz, 1H),7.47 (d, J=8.6 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.03 (dd, J=8.3, 1.3 Hz,1H), 6.99 (d, J=8.4 Hz, 1H), 3.78-3.72 (m, 2H), 3.51-3.45 (m, 2H),2.99-2.84 (m, 1H), 2.82-2.76 (m, 1H), 2.71-2.58 (m, 3H), 1.95-1.86 (m,1H), 1.81-1.72 (m, 1H), 1.06-0.94 (m, 6H).

Example 16[6-(4-Chloro-3-methyl-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂, 399.17; m/z found, 400.3 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (br s, 1H), 7.78 (dd, J=8.0, 2.5 Hz, 1H), 7.35 (d,J=8.8 Hz, 1H), 7.01 (d, J=2.5 Hz, 1H), 6.96-6.89 (m, 2H), 3.78-3.71 (m,2H), 3.56-3.46 (m, 2H), 2.93-2.79 (m, 1H), 2.64-2.57 (m, 1H), 2.52-2.39(m, 3H), 2.37 (s, 3H), 2.09-1.90 (m, 3H), 1.88-1.54 (m, 5H).

Example 17[6-(4-Chloro-3-methyl-phenoxy)-Pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₆ClN₃O₂, 387.90; m/z found, 388.3 [M+H]⁺.¹H NMR (CDCl₃): 8.24 (br s, 1H), 7.79 (dd, J=8.6, 2.3 Hz, 1H), 7.36 (d,J=8.6 Hz, 1H), 7.03 (d, J=2.8 Hz, 1H), 6.97-6.90 (m, 2H), 3.78-3.71 (m,2H), 3.53-3.45 (m, 2H), 2.99-2.83 (m, 1H), 2.83-2.74 (m, 1H), 2.71-2.57(m, 3H), 1.96-1.85 (m, 1H), 1.82-1.70 (m, 1H), 1.07-0.93 (m, 6H).

Example 18(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₂FN₃O₂, 355.17; m/z found, 356.4 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (d, J=2.3 Hz, 1H), 7.81-7.75 (m, 1H), 7.14-7.08 (m,4H), 6.94 (d, J=8.6 Hz, 1H), 3.77-3.70 (m, 2H), 3.54-3.39 (m, 2H),2.99-2.93 (m, 1H), 2.88-2.73 (m, 3H), 1.98-1.73 (m, 3H), 0.53-0.31 (m,4H).

Example 19(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-Pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.4 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (br s, 1H), 7.79 (dd, J=8.6, 2.8 Hz, 1H), 7.13-7.08(m, 4H), 6.95 (dd, J=8.1, 0.5 Hz, 1H), 3.81-3.71 (m, 2H), 3.58-3.46 (m,2H), 2.96-2.78 (m, 1H), 2.66-2.58 (m, 1H), 2.53-2.39 (m, 3H), 0.21-1.54(m, 8H).

Example 203-[5-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-pyridin-2-yloxy]-benzonitrile

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂, 376.19; m/z found, 377.5 [M+H]⁺.¹H NMR (CDCl₃): 8.22 (br s, 1H), 7.84 (dd, J=8.6, 2.8 Hz, 1H), 7.56-7.46(m, 3H), 7.44-7.38 (m, 1H), 7.03 (dd, J=8.3, 0.5 Hz, 1H), 3.82-3.71 (m,2H), 3.60-3.45 (m, 2H), 2.87-2.79 (m, 1H), 2.67-2.58 (m, 1H), 2.54-2.39(m, 3H), 2.12-1.52 (m, 8H).

Example 21(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₅N₃O₂, 351.19; m/z found, 352.5 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.78 (dd, J=8.8, 2.5 Hz, 1H), 7.45-7.39(m, 2H), 7.26-7.21 (m, 1H), 7.17-7.13 (m, 2H), 6.93 (d, J=8.5 Hz, 1H),3.81-3.71 (m, 2H), 3.58-3.47 (m, 2H), 2.94-2.79 (m, 1H), 2.66-2.58 (m,1H), 2.54-2.39 (m, 3H), 2.12-1.92 (m, 3H), 1.89-1.55 (m, 5H).

Example 22(4-Cyclopropyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-Pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₁₉H₂₀FN₃O₂, 341.15; m/z found, 342.5 [M+H]⁺.¹H NMR (CDCl₃): 8.24 (dd, J=2.3, 0.5 Hz, 1H), 7.81 (dd, J=8.6, 2.5 Hz,1H), 7.15-7.08 (m, 4H), 6.96 (dd, J=8.3, 0.8 Hz, 1H), 3.84-3.33 (m, 4H),2.76-2.49 (m, 4H), 1.70-1.61 (m, 4H), 0.54-0.37 (m, 4H).

Example 23[6-(3-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₂ClN₃O₂, 371.14; m/z found, 372.5 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (d, J=2.2 Hz, 1H), 7.83-7.77 (m, 1H), 7.37-7.32 (m,1H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.07-7.04 (m, 1H), 6.99-6.95(m, 1H), 3.78-3.71 (m, 2H), 3.53-3.47 (m, 2H), 2.98-2.93 (m, 1H),2.88-2.76 (m, 3H), 1.97-1.76 (m, 3H), 0.52-0.34 (m, 4H).

Example 24[6-(3-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₁ClN₃O₂, 385.16; m/z found, 386.2 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.81 (dd, J=8.2, 2.2 Hz, 1H), 7.36-7.32(m, 1H), 7.23-7.19 (m, 1H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 1H), 6.97(dd, J=8.5, 0.8 Hz, 1H), 3.81-3.72 (m, 2H), 3.58-3.47 (m, 2H), 2.97-2.80(m, 1H). 2.68-2.58 (m, 1H), 2.55-2.40 (m, 3H), 2.11-1.93 (m, 3H),1.90-1.55 (m, 5H).

Example 25[6-(4-Chloro-phenoxy)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₁ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (5, 1H), 7.80 (dd, J=8.5, 2.7 Hz, 1H), 7.40-7.35(m, 2H), 7.12-7.07 (m, 2H), 6.96 (d, J=8.2 Hz, 1H), 3.79-3.72 (m, 2H),3.57-3.47 (m, 2H), 2.95-2.79 (m, 1H), 2.65-2.58 (m, 1H), 2.53-2.39 (m,3H), 2.09-1.92 (m, 3H), 1.88-1.56 (m, 5H).

Example 26(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-difluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₃F₂N₃O₂F, 387.18; m/z found, 388.5[M+H]⁺. ¹H NMR (CDCl₃): 8.23 (s, 1H), 7.81 (dd, J=8.8, 2.5 Hz, 1H),7.24-7.16 (m, 1H), 7.05-6.96 (m, 2H), 6.92-6.86 (m, 1H), 3.80-3.73 (m,2H), 3.57-3.48 (m, 2H), 2.95-2.79 (m, 1H), 2.66-2.59 (m, 1H), 2.54-2.40(m, 3H), 2.11-1.92 (m, 3H), 1.89-1.60 (m, 5H).

Example 27(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-difluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₁F₂N₃O₂, 373.16; m/z found, 374.5 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (d, J=2.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.24-7.15 (m,1H), 7.06-6.95 (m, 2H), 6.93-6.87 (m, 1H), 3.78-3.70 (m, 2H), 3.54-3.45(m, 2H), 2.99-2.92 (m, 1H), 2.89-2.76 (m, 3H), 1.98-1.75 (m, 3H),0.53-0.33 (m, 4H).

Example 28[6-(3,4-Difluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₁F₂N₃O₂, 361.16; m/z found, 362.5 [M+H]⁺.¹H NMR (CDCl₃): 8.24 (dd, J=2.5, 1.0 Hz, 1H), 7.83 (dd, J=8.3, 2.3 Hz,1H), 7.24-7.16 (m, 1H), 7.06-6.97 (m, 2H), 6.92-6.87 (m, 1H), 3.88-3.36(m, 4H), 2.74 (h, J=6.8 Hz, 1H), 2.66-2.42 (m, 4H), 1.05 (d, J=6.6 Hz,1H).

Example 29(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(2-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.5 [M+H]⁺.¹H NMR (CDCl₃): 8.20 (br s, 1H), 7.81 (dd, J=8.6, 2.0 Hz, 1H), 7.26-7.16(m, 5H), 7.02 (dd, J=8.3, 1.0 Hz, 1H), 3.81-3.71 (m, 2H), 3.59-3.46 (m,2H), 2.96-2.78 (m, 1H), 2.66-2.58 (m, 1H), 2.54-2.39 (m, 3H), 2.11-1.91(m, 3H), 1.90-1.55 (m, 5H).

Example 30(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(2,4-difluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₃F₂N₃O₂, 387.18; m/z found, 388.5 [M+H]⁺.¹H NMR (CDCl₃): 8.18 (br s, 1H), 7.81 (dd, J=8.8, 2.5 Hz, 1H), 7.22-7.16(m, 1H), 7.03 (dd, J=8.5, 0.8 Hz, 1H), 6.99-6.89 (m, 2H), 3.80-3.72 (m,2H), 3.56-3.47 (m, 2H), 2.94-2.79 (m, 1H), 2.65-2.59 (m, 1H), 2.53-2.40(m, 3H), 2.10-1.92 (m, 3H), 1.92-1.56 (m, 5H).

Example 31(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₂FN₃O₂, 355.17; m/z found, 356.5 [M+H]⁺.¹H NMR (CDCl₃): 8.20 (d, J=2.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.26-7.1 (m,5H), 7.03 (d, J=8.6 Hz, 1H), 3.78-3.69 (m, 2H), 3.55-3.45 (m, 2H),2.98-2.91 (m, 1H), 2.88-2.75 (m, 3H), 1.97-1.75 (m, 3H), 0.53-0.33 (m,4H).

Example 32(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2,4-difluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₁F₂N₃O₂, 373.16; m/z found, 374.5 [M+H]⁺.¹H NMR (CDCl₃): 8.18 (d, J=2.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.24-7.16 (m,1H), 7.03 (d, J=8.6 Hz, 1H), 7.00-6.89 (m, 2H), 3.77-3.70 (m, 2H),3.53-3.45 (m, 2H), 2.98-2.93 (m, 1H), 2.87-2.75 (m, 3H), 1.98-1.75 (m,3H), 0.52-0.33 (m, 4H).

Example 33(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₃Cl₂N₃O₂, 419.12; m/z found, 420.5[M+H]⁺. ¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.83 (dd, J=8.3, 2.3 Hz, 1H),7.22 (dd, J=1.8, 1.8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.3,0.5 Hz, 1H), 3.82-2.60 (m, 1H), 2.55-2.41 (m, 3H), 2.12-1.94 (m, 3H),1.90-1.57 (m, 5H).

Example 34(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(2,5-difluoro-phenoxy)-Pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₁F₂N₃O₂, 373.16; m/z found, 374.5 [M+H]⁺.¹H NMR (CDCl₃): 8.20 (d, J=1.9 Hz, 1H), 7.84-7.79 (m, 1H), 7.18-7.12 (m,1H), 7.04 (d, J=8.5 Hz, 1H), 7.02-6.97 (m, 1H), 6.95-6.89 (m, 1H),3.78-2.71 (m, 2H), 3.53-3.46 (m, 2H), 2.98-2.93 (m, 1H), 2.87-2.76 (m,3H), 1.97-1.76 (m, 3H), 0.51-0.35 (m, 4H).

Example 35(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂N₃O₂, 405.10; m/z found, 406.4[M+H]⁺. ¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.85-7.79 (m, 1H), 7.23 (dd,J=1.9, 1.9 Hz, 1H), 7.09 (d, J=1.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H),3.78-3.72 (m, 2H), 3.53-3.47 (m, 2H), 2.94-2.89 (m, 1H), 2.89-2.77 (m,3H), 1.98-1.76 (m, 3H), 0.53-0.35 (m, 4H).

Example 36(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,5-difluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₃F₂N₃O₂, 387.18; m/z found, 388.5 [M+H]⁺.

Example 37(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₂FN₃O₂, 355.17; m/z found, 356.5 [M+H]⁺.¹H NMR (CDCl₃): 8.30-8.12 (m, 1H), 7.86-7.73 (m, 1H), 7.43-7.33 (m, 1H),7.03-7.83 (m, 4H), 3.84-3.65 (m, 1H), 3.57-3.36 (m, 3H), 3.00-2.92 (m,1H), 2.90-2.70 (m, 3H), 2.00-1.66 (m, 3H), 0.54-0.34 (m, 4H).

Example 38[6-(3-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₂, 357.19; m/z found, 358.5 [M+H]⁺.¹H NMR (CDCl₃): 8.32-8.21 (m, 1H), 7.86-7.76 (m, 1H), 7.42-7.32 (m, 1H),7.03-6.85 (m, 4H), 3.85-3.68 (m, 2H), 3.59-3.40 (m, 2H), 3.08-2.77 (m,2H), 2.73-2.58 (m, 3H), 2.02-1.86 (m, 2H), 1.15-0.89 (m, 6H).

Example 39(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.5 [M+H]⁺.¹H NMR (CDCl₃): 8.29-8.22 (m, 1H), 7.86-7.77 (m, 1H), 7.42-7.32 (m, 1H),7.01-6.87 (m, 4H), 3.84-3.72 (m, 2H), 3.59-3.46 (m, 2H), 2.98-2.78 (m,1H), 2.68-2.58 (m, 1H), 2.55-2.38 (m, 3H), 2.12-1.54 (m, 8H).

Example 40(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-Pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₃H₂₉N₃O₂S, 411.12; m/z found, 412.5 [M+H]⁺.¹H NMR (CDCl₃): 8.31-8.19 (m, 1H), 7.83-7.74 (m, 1H), 7.24-7.17 (m, 1H),7.03-6.88 (m, 3H), 3.84-3.66 (m, 2H), 3.62-3.45 (m, 2H), 2.99-2.77 (m,1H), 2.69-2.67 (m, 1H), 2.56-2.38 (m, 6H), 3.52 (5, 3H), 2.13-1.50 (m,8H).

Example 41(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₇N₃O₂S, 397.18; m/z found, 398.5 [M+H]⁺.¹H NMR (CDCl₃): 8.30-8.19 (m, 1H), 7.84-7.70 (m, 1H), 7.24-7.18 (m, 1H),7.05-6.88 (m, 3H), 3.84-3.68 (m, 2H), 3.56-3.46 (m, 2H), 3.01-2.91 (m,1H), 2.89-2.72 (m, 3H), 2.47 (s, 3H), 2.35 (s, 3H), 1.99-1.71 (m, 3H),0.56-0.26 (m, 4H).

Example 42(4-Isopropyl-[1,4]diazepan-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₉N₃O₂S, 399.20; m/z found, 400.5 [M+H]⁺.¹H NMR (CDCl₃): 8.29-8.20 (m, 1H), 7.81-7.65 (m, 1H), 7.24-7.18 (m, 1H),7.02-6.90 (m, 3H), 3.83-3.63 (m, 2H), 3.57-3.43 (m, 2H), 3.06-2.74 (m,2H), 2.72-2.56 (m, 3H), 2.47 (s, 3H), 3.52 (s, 3H), 1.98-1.87 (m, 1H),1.84-1.71 (m, 1H), 1.12-0.90 (m, 6H).

Example 43[6-(3,4-Dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone

Step A; (6-Bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone

To a solution of 6-bromo-pyridine-2-carboxylic acid (100.00 mg, 0.50mmol) in DCM (5.0 mL) was added 1-isopropylpiperazine (95.20 mg, 0.74mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC; 189.78 mg, 0.99 mmol), 1-hydroxybenzotriazole (HOBt;133.78 mg, 0.99 mmol), and iPr₂NEt (0.86 mL, 4.95 mmol). After 18 h atrt, the mixture was diluted with water and extracted with DCM.Purification by FCC provided the desired product (83.0 mg, 54%). MS(ESI): mass calcd. for C₁₃H₁₈BrN₃O, 311.06; m/z found, 312.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.69-7.59 (m, 2H), 7.56-7.52 (m, 1H), 3.84-3.76 (m, 2H),2.79-2.68 (m, 1H), 2.62 (t, J=5.1 Hz, 2H), 2.53 (t, J=5.1 Hz, 2H), 1.06(d, J=6.5 Hz, 6H). Assay 1 (Human H₃): K=1400 nM.

Step B

To a solution of(6-bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (76.7 mg,0.25 mmol) in DMF (2.5 mL) was added 3,4 dichlorophenol (40.07 mg, 0.25mmol) and K₂CO₃ (101.93 mg, 0.74 mmol). After 18 h at 120° C., themixture was cooled to rt, diluted with water, and extracted with DCM.Purification by FCC followed by reverse phase HPLC (basic conditions)provided the desired product (10.0 mg, 3.5%). MS (ESI): mass calcd. forC₁₉H₂₁Cl₂N₃O₂, 393.10; m/z found, 394.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.82(dd, J=8.2, 7.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=2.7 Hz, 1H),7.06-6.98 (m, 2H), 3.75-3.67 (m, 2H), 3.50-3.44 (m, 2H), 2.70-2.61 (m,1H), 2.55-2.48 (m, 2H), 2.23-2.15 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).

The compounds in Examples 44-52 were prepared using methods analogous tothose described in Example 43. Where trifluoroacetic acid salts wereobtained, purification was done using preparative HPLC (acidicconditions).

Example 44(4-Cyclopropyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone

Step A;(6-Bromo-pyridin-2-yl)-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₄H₁₈BrN₃O, 323.06; m/z found, 326.3 [M+H]⁺.¹H NMR (CDCl₃): 7.67-7.63 (m, 1H), 7.62-7.58 (m, 1H), 7.54-7.51 (m, 1H),3.80-3.73 (m, 2H), 3.62-3.53 (m, 2H), 3.00-2.95 (m, 1H), 2.92-2.81 (m,3H), 1.99-1.81 (m, 3H), 0.54-0.35 (m, 4H). Assay 1 (Human H₃): K_(i)=431nM.

Step B

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂N₃O₂, 405.10; m/z found, 406.4[M+H]⁺. ¹H NMR (CDCl₃): 7.85-7.78 (m, 1H), 7.49-7.40 (m, 2H), 7.29-7.24(m, 1H), 7.04-6.97 (m, 2H), 3.71-3.64 (m, 2H), 3.43-3.35 (m, 2H),2.91-2.85 (m, 1H), 2.75-2.69 (m, 1H), 2.64-2.59 (m, 1H), 2.44-2.38 (m,1H), 1.93-1.85 (m, 1H), 1.64-1.50 (m, 2H), 0.51-0.28 (m, 4H).

Example 45(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanone

Step A;(6-Bromo-pyridin-2-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₅H₂₀BrN₃O, 337.08; m/z found, 339.2 [M+H]⁺.¹H NMR (CDCl₃): 7.67-7.58 (m, 2H), 7.54-7.50 (m, 1H), 3.85-3.74 (m, 2H),3.69-3.52 (m, 2H), 3.01-2.86 (m, 1H), 2.69-2.44 (m, 4H), 2.14-1.53 (m,8H). Assay 1 (Human H₃): K_(i)=33 nM.

Step B

MS (ESI): mass calcd. for C₂₁H₂₃Cl₂N₃O₂, 419.12; m/z found, 420.4[M+H]⁺. ¹H NMR (CDCl₃): 7.86-7.78 (m, 1H), 7.50-7.39 (m, 2H), 7.28-7.23(m, 1H), 7.04-6.97 (m, 2H), 3.73-3.66 (m, 2H), 3.48-3.42 (m, 1H), 3.39(t, J=6.5 Hz, 1H), 2.91-2.58 (m, 1H), 2.57-2.51 (m, 1H), 2.91-2.58 (m,1H), 2.23-2.20 (m, 1H), 2.14-1.87 (m, 4H), 1.86-1.48 (m, 5H).

Example 46[6-(3,4-Dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

Step A;(6-Bromo-pyridin-2-yl)-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₄H₂₀BrN₃O, 325.08; m/z found, 328.3 [M+H]⁺.¹H NMR (CDCl₃): 7.68-7.58 (m, 2H), 7.54-7.50 (m, 1H), 3.82-3.72 (m, 2H),3.63-3.53 (m, 2H), 3.01-2.87 (m, 1H), 2.84-2.76 (m, 1H), 2.77-2.61 (m,3H), 2.02-1.78 (m, 2H), 1.08-0.95 (m, 6H). Assay 1 (Human H₃): K=752 nM.

Step B

MS (ESI): mass calcd. for C₂₀H₂₃Cl₂N₃O₂, 407.12; m/z found, 408.4[M+H]⁺. ¹H NMR (CDCl₃): 7.86-7.79 (m, 1H), 7.51-7.40 (m, 2H), 7.25 (d,J=2.7, 1 H), 7.03-6.96 (m, 2H), 3.73-3.67 (m, 2H), 3.65-3.57 (m, 2H),3.47-3.43 (m, 1H), 3.41-3.35 (m, 1H), 2.99-2.67 (m, 2H) 2.62-2.54 (m,1H), 2.45-2.32 (m, 2H), 1.98-1.41 (m, 2H), 1.00-0.92 (m, 6H).

Example 47[6-(4-Chloro-3-methyl-phenoxy)-pyridin-2-yl]-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.¹H NMR (MeOD): 8.04-7.94 (m, 1H), 7.62-7.39 (m, 2H), 7.25-7.10 (m, 2H),7.08-6.96 (m, 1H), 4.42-3.08 (m, 7H), 3.03-2.96 (m, 1H), 2.92-2.82 (m,0.5H), 2.59-2.50 (m, 0.5H), 2.44-2.35 (m, 3H), 2.28-2.04 (m, 1H),1.95-1.35 (m, 1H), 1.09-0.86 (m, 4H).

Example 48[6-(4-Chloro-3-methyl-phenoxy)-pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂, 399.17; m/z found, 400.5 [M+H]⁺.¹H NMR (MeOD): 8.09-7.90 (m, 1H), 7.63-7.37 (m, 2H), 7.26-7.10 (m, 2H),7.08-6.94 (m, 1H), 4.32-3.24 (m, 7H), 3.19-2.50 (m, 3H), 2.50-1.20 (m,7H), 1.98-1.67 (m, 3H).

Example 49[6-(4-Chloro-3-methyl-phenoxy)-Pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₆ClN₃O₂, 387.17; m/z found, 388.5 [M+H]⁺.¹H NMR (MeOD): 8.08-7.93 (m, 1H), 7.50-7.38 (m, 2H), 7.29-7.09 (m, 2H),7.07-6.96 (m, 1H), 4.18-3.86 (m, 1H), 3.86-3.40 (m, 4H), 3.41-2.82 (m,4H), 2.44-2.35 (m, 3H), 2.33-1.97 (m, 1H), 1.93-1.76 (m, 1H), 1.39-1.08(m, 6H).

Example 50[5-(3,4-Dichloro-phenoxy)-Pyridin-2-yl]-(4-isopropyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

Step A;(5-Bromo-pyridin-2-yl)-(4-isopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₄H₂₀BrN₃O, 326.08; m/z found, 328.4 [M+H]⁺.¹H NMR (CDCl₃): 8.64 (dd, J=2.4, 0.8 Hz, 1H), 7.93-7.89 (m, 1H),7.56-7.52 (m, 1H), 3.81-7.75 (m, 2H), 3.60-3.53 (m, 2H), 3.00-2.85 (m,1H), 2.83-2.77 (m, 1H), 2.72-2.60 (m, 3H), 1.97-1.90 (m, 1H), 1.84-1.72(m, 1H), 1.05-0.96 (m, 6H). Assay 1 (Human H₃): K=194 nM.

Step B

MS (ESI): mass calcd. for C₂₀H₂₃Cl₂N₃O₂, 407.12; m/z found, 408.4[M+H]⁺. ¹H NMR (MeOD): 8.45-8.34 (m, 1H), 7.87-7.71 (m, 1H), 7.62-7.55(m, 2H), 7.38-7.32 (m, 1H), 7.14-7.05 (m, 1H), 4.23-3.50 (m, 7H),3.45-3.27 (m, 2H), 2.39-2.10 (m, 2H), 1.44-1.34 (m, 6H).

Example 51(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanonetrifluoroacetic acid salt

Step A;(5-Bromo-pyridin-2-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₅H₂₀BrN₃O, 337.08; m/z found, 340.4 [M+H]⁺.¹H NMR (CDCl₃): 8.66-8.61 (m, 1H), 7.95-7.89 (m, 1H), 7.58-7.52 (m, 1H),3.82-3.76 (m, 2H), 3.65-3.55 (m, 2H), 2.98-2.82 (m, 1H), 2.67-2.60 (m,1H), 2.56-2.44 (m, 3H), 2.12-1.55 (m, 8H). Assay 1 (Human H₃): K=11 nM.

Step B

MS (ESI): mass calcd. for C₂₁H₂₃Cl₂N₃O₂, 419.12; m/z found, 420.4[M+H]⁺. ¹H NMR (MeOD): 8.49-8.31 (m, 1H), 7.92-7.72 (m, 1H), 7.70-7.53(m, 2H), 7.77-7.28 (m, 1H), 7.21-7.04 (m, 1H), 4.37-4.02 (m, 1H),3.97-3.02 (m, 8H), 2.52-2.06 (m, 6H), 2.01-1.71 (m, 2H).

Example 52(4-Cyclopropyl-[1,4]diazepan-1-yl)-[5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-methanonetrifluoroacetic acid salt

Step A;(5-Bromo-pyridin-2-yl)-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₄H₁₈BrN₃O, 323.06; m/z found, 324.4 [M+H]⁺.¹H NMR (CDCl₃): 8.66-8.62 (m, 1H), 7.95-7.89 (m, 1H), 7.58-7.51 (m, 1H),3.82-3.73 (m, 2H), 3.63-3.52 (m, 2H), 3.01-2.94 (m, 1H), 2.90-2.78 (m,3H), 2.01-1.78 (m, 3H), 0.54-0.34 (m, 4H). Assay 1 (Human H₃): K, =115nM.

Step B

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂N₃O₂, 405.10; m/z found, 406.4[M+H]⁺. ¹H NMR (MeOD): 8.43-8.32 (m, 1H), 7.87-7.72 (m, 1H), 7.64-7.42(m, 2H), 7.40-7.29 (m, 1H), 7.14-7.01 (m, 1H), 4.08-3.43 (m, 8H),3.08-2.93 (m, 1H), 2.48-2.09 (m, 2H), 1.12-0.94 (m, 4H).

Example 533-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitriletrifluoroacetic acid salt

Step A; 5-Bromo-pyridine-2-carboxylic acid methyl ester

A mixture of 5-bromo-2-pyridine carboxylic acid (26.2 g, 0.124 mol) andconc. H₂SO₄ (12.5 mL) in MeOH (250 mL) was heated to 60° C. and dilutedwith additional MeOH (250 mL). After 18 h at 60° C., the mixture wascooled to rt, diluted with DCM, and washed with a solution consisting of21 g KOH in 200 mL water, sat. K₂CO₃, and water. The organic layer wasdried and concentrated to give the title compound (21.4 g, 76%) as awhite solid. This material was used in the next step without furtherpurification.

Step B; 5-Bromo-1-oxo-pyridine-2-carboxylic acid methyl ester

To a 0° C. mixture of 5-bromo-pyridine-2-carboxylic acid methyl ester(10.1 g, 46.8 mmol) and urea hydrogen peroxide complex (9.33 g, 99.2mmol) in acetonitrile (150 mL) was added trifluoroacetic anhydride (13.0mL, 93.7 mmol). After 2 h, the mixture was poured into 0.5 M HCl andextracted with DCM. The organic layer was washed with satd. aq. NaHCO₃,dried, and concentrated. The residue was purified by FCC (ethyl acetate(EtOAc)/hexanes) to give the title compound (9.70 g, 89%) as a colorlessviscous oil. MS (ESI): mass calcd. for C₇H₆BrNO₃, 230.95; m/z found,232.2 [M+H]⁺. ¹H NMR (d⁶-acetone): 8.49-8.48 (m, 1H), 7.63-7.62 (m, 2H),3.89 (s, 3H).

Step C; 5-Bromo-6-cyano-pyridine-2-carboxylic acid methyl ester

A mixture of 5-bromo-1-oxo-pyridine-2-carboxylic acid methyl ester (9.43g, 40.6 mmol), TMSCN (54 mL), and dimethylcarbamyl chloride (38 mL) washeated at 50° C. for 16 h. The mixture was allowed to cool to rt and waspoured over ice water containing NaOH (40 g, 1 mol). The mixture wasextracted with DCM (2×), and the combined organic layers were dried andconcentrated to give the crude product as a red solid. Recrystallizationfrom hot MeOH and FCC (EtOAc/hexanes) of the concentrated mother liquortogether gave the title compound (7.51 g, 77%). ¹H NMR (d⁶-acetone):8.83 (d, J=8.4 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).

Step D; 5-Bromo-6-cyano-pyridine-2-carboxylic acid

To a solution of potassium trimethylsilanoate (0.80 g, 6.22 mmol) in THF(26 mL) was added 5-bromo-6-cyano-pyridine-2-carboxylic acid methylester (998 mg, 4.15 mmol). The mixture was heated at 50° C. for 3 h,then was cooled to rt and treated with HCl (4 N in dioxane; 1.60 mL).After 30 min, the mixture was concentrated. The residue was dissolved inhot EtOAc and filtered. The filtrate was concentrated to give the titlecompound (993 mg, >100%), which was used in the next step withoutfurther purification.

Step E;3-Bromo-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile

A mixture of 5-bromo-6-cyano-pyridine-2-carboxylic acid (875 mg, 3.85mmol), HOBt (882 mg, 6.53 mmol), and EDC (1.11 g, 5.80 mmol) in DMF (32mL) was stirred for 5 min and then treated with 1-isopropyl-piperazine(943 mg, 7.35 mmol). After 5 h, the mixture was diluted with DCM, washedwith 1 N NaOH and water, dried, and concentrated. Purification of theresidue by FCC gave a viscous foam that crystallized upon standing.Further purification by reverse-phase HPLC gave the title compound (476mg, 37%). MS (ESI): mass calcd. for C₁₄H₁₇BrN₄O, 336.06; m/z found,337.2 [M+H]⁺. ¹H NMR (d⁶-acetone): 8.43 (d, J=8.4 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 3.70-3.68 (m, 2H), 3.51-3.49 (m, 2H), 2.73 (septet, J=6.6Hz, 1H), 2.58-2.56 (m, 2H), 2.50-2.48 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).

Step F

A mixture of3-bromo-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile(54.4 mg), 3,4-dichlorophenol (76.8 mg), and anhydrous Cs₂CO₃ (350 mg)in DMSO (0.6 mL) was heated by microwave irradiation at 150° C. for 30min. The mixture was purified by HPLC to give the title compound (18.5mg, 31%) as the TFA salt. MS (ESI): mass calcd. for C₂₀H₂₀Cl₂N₄O₂,418.10; m/z found, 419.2 [M+H]⁺. ¹H NMR (MeOD): 8.00 (d, J=9.0 Hz, 1H),7.67 (d, J=8.4 Hz, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.51 (d, J=3.0 Hz, 1H),7.23-7.21 (dd, J=8.7, 2.4 Hz, 1H), 4.87-4.80 (br s, 1H), 4.59-4.48 (brs, 1H), 3.70-3.46 (m, 4H), 3.35-3.18 (br s, 3H), 1.41 (d, J=7.2 Hz, 6H).

Example 543-(3,4-Dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carboxylicacid amide trifluoroacetic acid salt

The title compound was obtained from Example 53 using methods similar tothose described in Example 62 (9.8 mg, 16%). MS (ESI): mass calcd. forC₂₀H₂₂Cl₂N₄O₃, 436.11; m/z found, 437.3 [M+H]⁺. ¹H NMR (MeOD): 7.97 (d,J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.31 (d,J=3.0 Hz, 1H), 7.06-7.04 (dd, J=8.7, 3.0 Hz, 1H), 4.6 (br s, 1H), 3.90(s, 2H), 3.69-3.55 (m, 3H), 3.55-3.46 (br s, 1H), 3.42-3.20 (br m, 3H),1.41 (d, J=7.2 Hz, 6H).

Example 556-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile

Step A; 5-Bromo-1-oxo-pyridine-2-carboxylic acid

To a 0° C. mixture of 5-bromo-picolinic acid (18.5 g, 91.6 mmol) andurea hydrogen peroxide complex (18.2 g, 0.194 mol) in acetonitrile (275mL) was added trifluoroacetic anhydride (26 mL, 0.187 mol). After 4.5 h,the mixture was treated with aq. Na₂S₂O₃ at 0° C., stirred for 10 min,and then extracted with DCM (300 mL×5). The combined organic layers wereconcentrated to give the crude product, which was suspended in boilingwater (500 mL) and filtered. The filtered solid was triturated withboiling MeOH (500 mL) twice, leaving a yellow solid. The aqueous andmethanolic extracts were combined and concentrated to dryness togive >100% of the acid as a tan solid. MS (ESI): mass calcd. forC₆H₄BrNO₃, 216.94; m/z found, 218.1 [M+H]⁺. ¹H NMR (d⁶-DMSO): 17.70 (s,1H), 9.19 (d, J=1.5 Hz, 1H), 8.18-8.12 (m, 2H).

Step B;(5-Bromo-1-oxo-pyridin-2-yl)-(4-cyclopropyl-[1,4]diazepan-1-yl)-methanone

A mixture of 5-bromo-1-oxo-pyridine-2-carboxylic acid (1.12 g, 5.15mmol), HOBt (1.17 g, 8.69 mmol), and EDC (1.56 g, 8.14 mmol) in DMF (32mL) was stirred for 5 min and then treated with1-cyclopropyl-[1,4]diazepane dihydrochloride (1.38 g, 6.48 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 2.3 mL, 15.4 mmol). After 22 h,the mixture was diluted with DCM and washed with 1 N NaOH and water. Theorganic layer was dried and concentrated. The residue was purified byFCC to give the title compound (1.13 g, 65%). MS (ESI): mass calcd. forC₁₄H₁₈BrN₃O₂, 339.06; m/z found, 340.2 [M+H]⁺.

Step C;3-Bromo-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile

The title compound (76%) was prepared using methods analogous to thosedescribed for Example 53, Step C. MS (ESI): mass calcd. for C₁₅H₁₇BrN₄O,348.0586; m/z found, 349.6 [M+H]⁺. ¹H NMR (d⁶-acetone): 8.42 (d, J=8.4Hz, 1H), 7.83-7.81 (m, 1H), 3.70-3.68 (m, 2H), 3.55-3.52 (m, 2H),2.93-2.91 (m, 1H), 2.87-2.80 (m, 3H), 1.96-1.87 (m, 2H), 1.84-1.80 (m,1H), 0.46-0.44 (m, 1H), 0.43-0.41 (m, 1H), 0.37-0.35 (m, 1H), 0.32-0.30(m, 1H).

Step D

The title compound (71%) was prepared using methods analogous to thosedescribed for Example 53, Step F, with purification by FCC. MS (ESI):mass calcd. for C₂₂H₂₄N₄O₂S, 408.16; m/z found, 409.7 [M+H]⁺. ¹H NMR(d⁶-acetone): 7.87-7.85 (dd, J=8.7, 3.6 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H),7.43 (d, J=8.4 Hz, 2H), 7.26 (d, J=9.0 Hz, 2H), 3.70-3.68 (m, 2H),3.61-3.58 (m, 2H), 3.40-3.37 (m, 3H), 2.92-2.88 (m, 2H), 2.85-2.81 (m,2H), 2.77-2.70 (m, 3H), 2.54 (s, 3H), 1.96-1.83 (m, 4H), 1.75-1.71 (m,1H), 0.46-0.44 (m, 1H), 0.43-0.40 (m, 1H), 0.37-0.35 (m, 1H), 0.33-0.30(m, 2H).

The compounds in Examples 56-61 were prepared using methods analogous tothose described for Example 55, with exceptions where noted.

Example 566-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(pyridin-3-yloxy)-pyridine-2-carbonitrilehydrochloride salt

MS (ESI): mass calcd. for C₂₀H₂₁N₅O₂, 363.18; m/z found, 364.7 [M+H]⁺.¹H NMR (d⁶-acetone): 8.62 (d, J=2.5 Hz, 1H), 8.56-8.55 (dd, J=4.8, 1.5Hz, 1H), 7.90-7.88 (dd, J=8.8, 3.5 Hz, 1H), 7.78-7.75 (m, 1H), 7.63 (d,J=9.0 Hz, 1H), 7.56-7.54 (dd, J=8.5, 5.0 Hz, 1H), 3.70 (m, 2H),3.62-3.58 (m, 2H), 2.93-2.88 (m, 2H), 2.85-2.81 (m, 2H), 1.96-1.83 (m,3H), 0.47-0.41 (m, 2H), 0.38-0.35 (m, 1H), 0.33-0.31 (m, 1H). The freebase was dissolved in excess HCl (1.25 M in MeOH) and concentrated togive the hydrochloride salt.

Example 573-(4-Chloro-3-methyl-phenoxy)-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₂H₂₃ClN₄O₂, 410.15; m/z found, 411.1 [M+H]⁺.¹H NMR (CDCl₃): 7.86 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.27 (d,J=9.9 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.5, 2.6 Hz, 1H),3.78-3.74 (m, 2H), 3.70-3.64 (m, 2H), 2.98-2.94 (m, 2H), 2.88-2.83 (m,2H), 2.39 (s, 3H), 1.98-1.86 (m, 3H), 0.52-0.36 (m, 4H).

Example 586-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(3,4-dichloro-phenoxy)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₁H₂₀Cl₂N₄O₂, 431.31; m/z found, 432.9[M+H]⁺. ¹H NMR (CDCl₃): 7.92-7.89 (m, 1H), 7.54 (dd, J=8.7, 0.6 Hz, 1H),7.34 (dd, J=8.8, 1.1 Hz, 1H), 7.27-7.25 (m, 1H), 7.00 (ddd, J=8.8, 2.8,0.9 Hz, 1H), 3.79-3.75 (m, 2H), 3.70-3.64 (m, 2H), 2.99-2.94 (m, 2H),2.89-2.83 (m, 2H), 1.98-1.85 (m, 3H), 0.52-0.37 (m, 4H).

Example 596-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-fluoro-phenoxy)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂, 380.42; m/z found, 381.5 [M+H]⁺.¹H NMR (CDCl₃): 7.84 (d, J=8.9 Hz, 1H), 7.22 (dd, J=8.8, 0.4 Hz, 1H),7.17-7.07 (m, 4H), 3.79-3.70 (m, 2H), 3.68-3.63 (m, 2H), 2.97-2.91 (m,2H), 2.87-2.81 (m, 2H), 1.97-1.83 (m, 3H), 0.50-0.34 (m, 4H).

Example 606-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(3-fluoro-phenoxy)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂, 380.42; m/z found, 381.5 [M+H]⁺.¹H NMR (CDCl₃): 7.88 (d, J=8.8 Hz, 1H), 7.42 (dd, J=14.7, 8.2 Hz, 1H),7.33 (dd, J=8.9, 0.8 Hz, 1H), 7.05-6.95 (m, 1H), 6.92-6.83 (m, 2H),3.78-3.73 (m, 2H), 3.69-3.63 (m, 2H), 2.98-2.93 (m, 2H), 2.88-2.82 (m,2H), 1.97-1.85 (m, 3H), 0.51-0.35 (m, 4H).

Example 616-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(2-fluoro-phenoxy)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂, 380.42; m/z found, 381.5 [M+H]⁺.¹H NMR (CDCl₃): 7.84 (d, J=8.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.27-7.21 (m,3H), 7.17 (dd, J=8.8, 1.1 Hz, 1H), 3.76-3.70 (m, 2H), 3.68-3.62 (m, 2H),2.96-2.92 (m, 2H), 2.86-2.81 (m, 2H), 1.95-1.84 (m, 3H), 0.49-0.34 (m,4H).

Example 626-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carboxylicacid amide

A mixture of6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile(171.0 mg), 28% aq. NH₃ (5 mL), and 30% aq. H₂O₂ (1.0 mL) in MeOH (4.0mL) was stirred for 1.5 h. The mixture was diluted with DCM and washedwith satd. aq. Na₂S₂O₃. The organic layer was dried and concentrated.The residue was purified by reverse-phase HPLC followed by FCC to givethe title compound (46.4 mg, 26%). MS (ESI): mass calcd. forC₂₂H₂₆N₄O₃S, 426.17; m/z found, 427.8 [M+H]⁺. ¹H NMR (d⁶-acetone):7.74-7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (br s, 1H), 7.51-7.49 (dd,J=8.5, 1.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.82(br s, 1H), 3.71-3.68 (m, 2H), 3.65-3.61 (m, 2H), 2.93-2.88 (m, 2H),2.85-2.80 (m, 2H), 2.49 (s, 3H), 1.96-1.80 (m, 3H), 0.46-0.44 (m, 1H),0.42-0.40 (m, 1H), 0.37-0.36 (m, 1H), 0.32-0.30 (m, 1H).

Example 636-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(pyridin-3-yloxy)-pyridine-2-carboxylicacid amide

The title compound (67%) was prepared using methods analogous to thosedescribed for Example 62. MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃, 381.18;m/z found, 382.7 [M+H]⁺. ¹H NMR (d⁶-acetone): 8.37 (d, J=2.4 Hz, 1H),8.35-8.34 (dd, J=4.0, 1.6 Hz, 1H), 7.81-7.78 (dd, J=8.8, 2.8 Hz, 1H),7.69-7.67 (m, 1H), 7.61 (br s, 1H), 7.41-7.35 (m, 2H), 6.83 (br s, 1H),3.72-3.69 (m, 2H), 3.65-3.60 (m, 2H), 2.94-2.80 (m, 5H), 1.96-1.82 (m,3H), 0.48-0.44 (m, 1H), 0.42-0.40 (m, 1H), 0.38-0.34 (m, 1H), 0.33-0.29(m, 1H).

Example 64[6-Aminomethyl-5-(3,4-dichloro-phenoxy)-pyridin-2-yl]-(4-isopropyl-piperazin-1-yl)-methanonetrifluoroacetic acid salt

A mixture of3-(3,4-dichloro-phenoxy)-6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-2-carbonitrile(20.0 mg, 0.038 mmol) and CoCl₂.6H₂O (29.7 mg, 0.125 mmol) in THF/water(2:1; 0.6 mL) was stirred for 5 min and then treated with NaBH₄ (34.3mg, 0.907 mmol). After 6 h, the mixture was diluted with DCM, washedwith 1 N NaOH, dried over Na₂CO₃, and concentrated. Reverse-phase HPLCgave the desired product as the TFA salt (4.7 mg, 19%). MS (ESI): masscalcd. for C₂₀H₂₄Cl₂N₄O₂, 422.13; m/z found, 423.3 [M+H]⁺. ¹H NMR(MeOD): 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.47 (d, J=9.0Hz, 1H), 7.42 (d, J=3.0 Hz, 1H), 7.16-7.14 (dd, J=8.7, 2.4 Hz, 1H), 4.47(s, 2H), 3.74-3.60 (m, 4H), 3.52-3.38 (br s, 2H), 3.36-3.10 (br s, 3H),1.41 (d, J=6.6 Hz, 6H).

The compounds in Examples 65-83 were prepared using methods analogous tothose described in the preceding examples, except where otherwise noted.

Example 65(4-Cyclopentyl-[1,4]diazepan-1-yl)-(6-phenoxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₇N₃O₂, 365.21; m/z found 366.5 [M+H]⁺. ¹HNMR (CDCl₃): 8.33-7.25 (m, 1H), 7.85-7.78 (m, 1H), 7.48-7.42 (m, 2H),7.30-7.24 (m, 1H), 7.20-7.13 (m, 2H) 6.96 (d, J=8.5 Hz, 1H), 3.94-3.72(m, 2H), 3.65-3.50 (m, 2H), 3.50-3.10 (m, 5H), 2.15-1.20 (m, 10H).

Example 66(4-Cyclopentyl-[1,4]diazepan-1-yl)-[6-(3,4-dichloro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₅Cl₂N₃O₂, 433.13; m/z found, 434.5[M+H]⁺. ¹H NMR (CDCl₃): 8.27-8.24 (m, 1H), 7.84 (dd, J=8.5, 2.2 Hz, 1H),7.49 (d, J=8.5 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.06 (d, J=2.7 Hz, 1H),7.03-7.00 (m, 1H), 3.84-7-3.72 (m, 2H), 3.01-2.81 (m, 2H), 2.80-2.66 (m,3H), 2.05-1.27 (m, 10H).

Example 67(4-Cyclopentyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₆FN₃O₂, 383.20; m/z found, 384.5 [M+H]⁺.¹H NMR (CDCl₃): 8.30-8.20 (m, 1H), 8.87-7.76 (m, 1H), 7.15-7.09 (m, 4H),6.97 (d, J=8.5 Hz, 1H), 3.87-3.71 (m, 2H), 3.62-3.47 (m, 2H), 3.10-2.67(m, 5H), 2.15-1.24 (m, 10H).

Example 68[5-(4-Chloro-phenoxy)-pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

To a mixture of(5-bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (175 mg,0.52 mmol) in DMA (2.5 mL) was added 4-chlorophenol (133 mg, 1.03 mmol)and Cs₂CO₃ (336 mg, 1.03 mmol). The mixture was heated at 200° C. for 90min and cooled to rt. Water was added and mixture was extracted withDCM. The organic layer was concentrated and the residue was purified byFCC, followed by reverse phase HPLC, to give the title compound (108 mg,42%). MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5[M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.27 (m, 1H), 7.71-7.62 (m, 1H), 7.40-7.29(m, 3H), 7.05-6.97 (m, 2H), 3.86-3.76 (m, 2H), 3.75-3.68 (m, 1H),3.68-3.62 (m, 2H), 3.00-2.84 (m, 1H), 2.71-2.63 (m, 1H), 2.62-2.46 (m,2H), 2.13-1.96 (m 3H), 1.96-1.77 (m, 3H), 1.76-1.53 (m, 2H).

Example 69(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(4-fluoro-phenoxy)-pyridin-2-yl]-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.5 [M+H]⁺.¹H NMR (MeOD): 8.37-8.29 (m, 1H), 7.84-7.69 (m, 1H), 7.51-7.44 (m, 1H),7.27-7.13 (m, 4H), 4.35-4.03 (m, 1H), 3.93-3.05 (m, 8H), 2.45-2.17 (m,6H), 1.97-1.73 (m, 2H).

Example 70[5-(3-Chloro-phenoxy)-Pyridin-2-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.¹H NMR (MeOD): 8.42-8.33 (m, 1H), 7.82-7.78 (m, 1H), 7.60-7.52 (m, 1H),7.49-7.41 (m, 1H), 7.32-7.25 (m, 1H), 7.21-7.17 (m, 1H), 7.11-7.06 (m,1H), 7.38-4.05 (m, 1H), 3.96-3.02 (m, 8H), 2.47-2.13 (m, 6H), 1.96-1.73(m, 2H).

Example 71(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(3-fluoro-phenoxy)-pyridin-2-yl]-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.18; m/z found, 370.5 [M+H]⁺.¹H NMR (MeOD): 8.44-8.34 (m, 1H), 7.82-7.78 (m, 1H), 7.62-7.54 (m, 1H),7.52-7.43 (m, 1H), 7.07-6.99 (m, 1H), 6.99-6.90 (m, 2H), 4.39-4.03 (m,1H), 3.96-3.03 (m, 8H), 2.46-2.16 (m, 6H), 1.98-1.76 (m, 2H).

Example 72(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(2-fluoro-phenoxy)-pyridin-2-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.18; m/z found, 370.5 [M+H]⁺.¹H NMR (CDCl₃): 8.36-8.26 (m, 1H), 7.68-7.60 (m, 1H), 7.31-7.12 (m, 4H),3.84-3.75 (m, 2H), 3.72-3.67 (m, 1H), 3.67-3.61 (m, 1H), 3.0-2.82 (m,1H), 2.67-2.61 (m, 1H), 2.58-2.44 (m, 3H), 2.11-1.95 (m, 3H), 1.93-1.74(m, 3H), 1.74-1.54 (m, 2H).

Example 73[6-(2-Chloro-phenoxy)-Pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.

Example 74(4-Cyclopentyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.5 [M+H]⁺.

Example 75[6-(2-Chloro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₂ClN₃O₂, 359.14; m/z found, 360.5 [M+H]⁺.

Example 76[6-(2-Chloro-phenoxy)-Pyridin-3-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.

Example 77[6-(4-Chloro-phenoxy)-Pyridin-3-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃O₂, 385.16; m/z found, 386.5 [M+H]⁺.

Example 784-Cyclopentyl-piperazin-1-yl)-[6-(2-fluoro-phenoxy)-Pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃O₂, 369.19; m/z found, 370.5 [M+H]⁺.

Example 79(4-Cyclobutyl-piperazin-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₀H₂₂FN₃O₂, 355.17; m/z found, 356.5 [M+H]⁺.

Example 80[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₂, 329.15; m/z found, 330.5 [M+H]⁺.

Example 816-(4-Cyclopropyl-[1,4]diazepane-1-carbonyl)-3-phenoxy-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂, 362.17; m/z found, 363.5 [M+H]⁺.¹H NMR (CDCl₃): 7.85 (d, J=8.9 Hz, 1H), 7.50-7.44 (m, 2H), 7.34-7.29 (m,1H), 7.26 (t, J=4.5 Hz, 1H), 7.14-7.10 (m, 2H), 3.79-3.74 (m, 2H),3.72-3.65 (m, 2H), 3.00-2.94 (m, 2H), 2.89-2.84 (m, 2H), 1.99-1.85 (m,3H), 0.52-0.37 (m, 4H).

Example 826-(4-Cyclobutyl-[1,4]diazepane-1-carbonyl)-3-(4-fluoro-phenoxy)-pyridine-2-carbonitrile

MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₂, 394.18; m/z found, 395.5 [M+H]⁺.¹H NMR (CDCl₃): 7.93-7.81 (m, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.19-7.13 (m,2H), 7.13-7.08 (m, 2H), 3.82-3.76 (m, 2H), 3.75-3.67 (m, 2H), 2.99-2.87(m, 1H), 2.67-2.61 (m, 2H), 2.55-2.47 (m, 2H), 2.11-1.93 (m, 4H),1.91-1.76 (m, 2H), 1.75-1.59 (m, 2H).

Example 83(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenylsulfanyl)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃OS, 385.16; m/z found, 386.5 [M+H]⁺.¹H NMR (CDCl₃): 8.48-8.42 (m, 1H), 7.64-7.56 (m, 2H), 7.54 (dd, J=8.2,2.2 Hz, 1H), 7.21-7.12 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 3.81-3.69 (m,2H), 3.56-3.43 (m, 2H), 2.96-2.77 (m, 1H), 2.65-2.56 (m, 1H), 2.54-2.47(m, 1H), 2.46-2.39 (m, 2H), 2.11-1.90 (m, 3H), 1.88-1.54 (m, 5H).

The compounds in Examples 84-93 were prepared using methods analogous tothose described in the preceding examples.

Example 84(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(4-fluoro-phenylsulfanyl)-pyridin-2-yl]-methanonetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₂₄FN₃OS, 385.50; m/z found, 386.5 [M+H]⁺.¹H NMR (MeOD): 8.39-8.34 (m, 1H), 7.55-7.43 (m, 4H), 7.14-7.06 (m, 2H),3.85-3.73 (m, 2H), 3.69-3.63 (m, 1H), 3.60 (t, J=6.5 Hz, 1H), 2.98-2.83(m, 1H), 2.6-2.61 (m, 1H), 2.59-2.45 (m, 3H), 2.12-1.95 (m, 3H),1.94-1.76 (m, 3H), 1.75-1.54 (m, 2H).

Example 85[6-(4-Chloro-phenylsulfanyl)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃OS, 401.13; m/z found, 402.5 [M+H]⁺.¹H NMR (CDCl₃): 8.50-8.43 (m, 1H), 7.58-7.51 (m, 3H), 7.46-7.39 (m, 2H),6.94 (d, J=8.2 Hz, 1H), 3.81-3.70 (m, 2H), 3.55-3.42 (m, 2H), 2.96-2.79(m, 1H), 2.66-2.57 (m, 1H), 2.53-2.47 (m, 1H), 2.47-2.38 (m, 2H),2.13-1.90 (m, 3H), 1.90-1.55 (m, 5H).

Example 86(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenylsulfanyl-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₅N₃OS, 367.17; m/z found, 368.5 [M+H]⁺.¹H NMR (CDCl₃): 8.50-8.44 (m, 1H), 7.65-7.57 (m, 2H), 7.55-7.50 (m, 1H),7.49-7.42 (m, 3H), 6.88 (d, J=8.1 Hz, 1H), 3.80-3.69 (m, 2H), 3.54-3.43(m, 2H), 2.96-2.78 (m, 1H), 2.65-2.56 (m, 1H), 2.53-2.46 (m, 1H),2.46-2.39 (m, 2H), 2.11-1.91 (m, 3H), 1.90-1.54 (m, 6H).

Example 87(4-Cyclopentyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₃H₂₉N₃O₂S, 411.20; m/z found, 412.3 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (dd, J=2.4, 0.8 Hz, 1H), 7.79 (dd, J=8.6, 2.4 Hz,1H), 7.21 (d, J=8.2 Hz, 1H), 7.03-6.92 (m, 3H), 3.99-3.33 (m, 4H),2.62-2.39 (m, 7H), 2.35 (s, 3H), 1.91-1.79 (m, 2H), 1.76-1.63 (m, 3H),1.63-1.48 (m, 2H), 1.47-1.33 (m, 2H).

Example 88(4-Isopropyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂S, 385.18; m/z found, 386.3 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (dd, J=2.4, 0.8 Hz, 1H), 7.81-7.77 (m, 1H),7.23-7.20 (m, 1H), 7.02-6.92 (m, 3H), 3.89-3.37 (m, 4H), 2.80-2.67 (m,1H), 2.65-2.42 (m, 7H), 2.35 (s, 3H), 1.04 (d, J=6.5 Hz, 6H).

Example 89[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.17; m/z found, 344.3 [M+H]⁺.¹H NMR (CDCl₃): 8.25-8.22 (m, 1H), 7.83-7.79 (m, 1H), 7.12-7.11 (m, 2H),7.11-7.10 (m, 2H), 6.96 (dd, J=8.4, 0.8 Hz, 1H), 3.93-3.32 (m, 4H),2.79-2.67 (m, 1H), 2.66-2.39 (m, 4H), 1.04 (d, J=6.5 Hz, 6H).

Example 904-Ethyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.17; m/z found, 344.5 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (br s, 1H), 7.88-7.77 (m, 1H), 7.19-7.06 (m, 4H),6.97 (d, J=8.2 Hz, 1H), 3.86-3.72 (m, 2H), 3.63-3.46 (m, 2H), 2.87-2.77(m, 1H), 2.74-2.51 (m, 5H), 2.03-1.95 (m, 1H), 1.92-1.82 (m, 1H),1.16-1.00 (m, 3H).

Example 91(4-Cyclobutyl-[1,4]diazepan-1-yl)-(5-phenylsulfanyl-pyridin-2-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₅N₃O_(S), 367.17; m/z found, 368.5[M+H]⁺. ¹H NMR (CDCl₃): 8.44-8.41 (m, 1H), 7.61-7.49 (m, 2H), 7.47-7.32(m, 5H), 3.82-3.75 (m, 2H), 3.68-3.56 (m, 2H), 2.96-2.81 (m, 1H),2.65-2.60 (m, 1H), 2.55-2.43 (m, 3H), 2.10-1.94 (m, 3H), 1.90-1.74 (m,3H), 1.73-1.54 (m, 2H).

Example 92[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₂, 329.15; m/z found, 330.5 [M+H]⁺.¹H NMR (CDCl₃): 8.30-8.21 (m, 1H), 7.86-7.76 (m, 1H), 7.17-7.18 (m, 4H),6.97 (d, J=8.5 Hz, 1H), 3.85-3.75 (m, 2H), 3.63-3.57 (m, 1H), 3.57-3.51(m, 1H), 2.78-2.73 (m, 1H), 2.68-2.63 (m, 1H), 2.62-2.54 (m, 2H),2.45-2.32 (m, 3H), 2.06-1.97 (m, 1H), 1.94-1.86 (m, 1H).

Example 93[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isobutyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₂, 357.19; m/z found, 358.5 [M+H]⁺.¹H NMR (CDCl₃): 8.23 (dd, J=2.5, 0.9 Hz, 1H), 7.80 (dd, J=8.8, 2.2 Hz,1H), 7.13-7.09 (m, 4H), 6.96 (dd, J=8.3, 0.8 Hz, 1H), 3.86-3.37 (br d,4H), 2.53-2.28 (br s, 4H), 2.10 (d, J=8.1 Hz, 2H), 1.83-1.71 (m, 1H),0.90 (d, J=6.3 Hz, 6H).

The compounds in Examples 94-105 were prepared using methods analogousto those described in the preceding examples.

Example 94(4-Cyclobutyl-[1,4]diazepan-1-yl)-(5-phenylsulfanyl-pyridin-2-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₅N₃OS, 367.2; m/z found, 368.5 [M+H]⁺. ¹HNMR (CDCl₃): 8.45-8.39 (m, 1H), 7.60-7.55 (m, 1H), 7.55-7.50 (m, 1H),7.47-7.42 (m, 2H), 7.42-7.33 (m, 3H), 3.82-3.75 (m, 2H), 3.67-3.63 (m,1H), 3.62-3.57 (m, 1H), 2.96-2.80 (m, 1H), 2.65-2.60 (m, 1H), 2.55-2.43(m, 3H), 2.10-1.94 (m, 3H), 1.91-1.73 (m, 3H), 1.72-1.54 (m, 2H).

Example 95(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenylsulfanyl-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₅N₃OS, 367.2; m/z found, 368.5 [M+H]⁺. ¹HNMR (CDCl₃): 8.51-8.43 (m, 1H), 7.65-7.58 (m, 2H), 7.55-7.49 (m, 1H),7.49-7.42 (m, 3H), 6.88 (d, J=8.4 Hz, 1H), 3.80-3.69 (m, 2H), 3.56-3.43(m, 2H), 2.95-2.77 (m, 1H), 2.65-2.56 (m, 1H), 2.53-2.36 (m, 3H),2.11-1.91 (m, 3H), 1.90-1.54 (m, 5H).

Example 96[6-(4-Chloro-phenylsulfanyl)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₄ClN₃OS, 401.1; m/z found, 402.5 [M+H]⁺.¹H NMR (CDCl₃): 8.49-8.43 (m, 1H), 7.58-7.50 (m, 3H), 7.45-7.42 (m, 1H),7.42-7.40 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 3.79-3.71 (m, 2H), 3.54-3.44(m, 2H), 2.96-2.78 (m, 1H), 2.67-2.57 (m, 1H), 2.55-2.38 (m, 3H),2.13-1.91 (m, 3H), 1.90-1.53 (m, 5H).

Example 97(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenylsulfanyl)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₄FN₃OS, 385.2; m/z found, 386.5 [M+H]⁺.¹H NMR (CDCl₃): 8.48-8.44 (m, 1H), 7.63-7.57 (m, 2H), 7.54 (dd, J=8.2,2.2 Hz, 1H), 7.19-7.11 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 3.80-3.70 (m,2H), 3.55-3.34 (m, 2H), 2.95-2.78 (m, 1H), 2.65-2.57 (m, 1H), 2.53-2.46(m, 1H), 2.46-2.38 (m, 2H), 2.10-1.91 (m, 3H), 1.89-1.54 (m, 5H).

Example 98(4-Ethyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.2; m/z found, 344.5 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.88-7.56 (m, 1H), 7.18-7.10 (m, 4H),6.97 (d, J=8.2 Hz, 1H), 3.87-3.72 (m, 2H), 3.63-3.48 (m, 2H), 2.87-2.76(m, 1H), 2.75-2.49 (m, 5H), 2.03-1.94 (m, 1H), 1.92-1.82 (m, 1H),1.16-1.00 (m, 3H).

Example 99[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.2; m/z found, 344.5 [M+H]⁺.¹H NMR (CDCl₃): 8.24-8.21 (m, 1H), 7.83-7.79 (m, 1H), 7.12 (br s, 2H),7.11-7.08 (m, 2H), 6.98-6.94 (m, 1H), 3.93-3.63 (m, 2H), 3.61-3.36 (m,2H), 2.80-2.67 (m, 1H), 2.66-2.37 (m, 4H), 1.04 (d, J=6.5 Hz, 6H).

Example 100(4-Cyclopentyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass cald. for C₂₃H₂₉N₃O₂S, 411.2; m/z found, 412.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.26 (dd, J=2.4, 0.8 Hz, 1H), 7.83-7.77 (m, 1H), 7.21 (d,J=8.4 Hz, 1H), 7.03-6.92 (m, 3H), 3.95-3.36 (m, 4H), 2.69-2.41 (m, 7H),2.35 (s, 3H), 1.93-1.80 (m, 2H), 1.78-1.62 (m, 3H), 1.62-1.49 (m, 2H),1.46-1.32 (m, 2H).

Example 101(4-Isopropyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂S, 385.2; m/z found, 386.3 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (dd, J=2.4, 0.8 Hz, 1H), 7.82-7.76 (m, 1H), 7.21(d, J=8.2 Hz, 1H), 7.01-6.94 (m, 3H), 3.88-3.35 (m, 4H), 2.80-2.68 (m,1H), 2.66-2.41 (m, 7H), 2.35 (m, 3H), 1.05 (d, J=6.5 Hz, 6H).

Example 102(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-o-tolyloxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂S, 365.2; m/z found, 366.3 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.82-7.77 (m, 1H), 7.33-7.29 (m, 1H),7.28-7.24 (m, 1H), 7.21-7.16 (m, 1H), 7.09-7.05 (m, 1H), 6.94-6.90 (m,1H), 3.81-3.73 (m, 2H), 3.60-3.50 (m, 2H), 2.98-2.82 (m, 1H), 2.67-2.59(m, 1H), 2.54-2.39 (m, 3H), 2.19 (s, 3H), 2.12-1.93 (m, 3H), 1.92-1.54(m, 5H).

Example 103(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-m-tolyloxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂S, 365.2; m/z found, 366.3 [M+H]⁺.¹H NMR (CDCl₃): 8.26 (br s, 1H), 7.78 (dd, J=8.4, 2.4 Hz, 1H), 7.32-7.27(m, 1H), 7.07-7.02 (m, 1H), 6.97-6.90 (m, 3H), 3.81-3.71 (m, 2H),3.59-3.47 (m, 2H), 2.95-2.78 (m, 1H), 2.66-2.58 (m, 1H), 2.54-2.39 (m,3H), 2.37 (s, 3H), 2.11-1.91 (m, 3H), 1.90-1.56 (m, 5H).

Example 104(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-p-tolyloxy-pyridin-3-yl)-methanone

MS (ESI): mass calcd. for C₂₁H₂₇N₃O₂S, 365.2; m/z found, 366.3 [M+H]⁺.¹H NMR (CDCl₃): 8.24 (br s, 1H), 7.80-7.73 (m, 1H), 7.24-7.18 (m, 2H),7.05-7.00 (m, 2H), 6.94-6.90 (m, 1H), 3.81-3.70 (m, 2H), 3.59-3.46 (m,2H), 2.95-2.78 (m, 1H), 2.67-2.57 (m, 1H), 2.55-2.40 (m, 3H), 2.37 (s,3H), 2.13-1.91 (m, 3H), 1.91-1.54 (m, 5H).

Example 105(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₇N₃O₂S, 397.2; m/z found, 398.3 [M+H]⁺.¹H NMR (CDCl₃): 8.25 (br s, 1H), 7.78 (dd, J=8.4, 2.4 Hz, 1H), 7.36-7.29(m, 2H), 7.14-7.05 (m, 2H), 6.97-6.90 (m, 1H), 3.83-3.70 (m, 2H),3.59-3.46 (m, 2H), 2.97-2.77 (m, 1H), 2.66-2.58 (m, 1H), 2.55-2.38 (m,6H), 2.11-1.91 (m, 3H), 1.91-1.52 (m, 5H).

Example 106(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

5-Bromo-2-(4-fluoro-phenoxy)-pyridine (27.2 mg, 0.102 mmol) wasdissolved in Et₂O (0.8 mL). The mixture was cooled to −78° C. n-Butyllithium (0.040 mL, 2.5 M in hexanes) was added and the reaction mixturewas stirred for 5 min at −78° C. CO₂ gas (from dry ice, passed through 4Å molecular sieves) was bubbled through the mixture and the reaction wasallowed to warm to 23° C. over 3 min. The solvents were removed bydistillation then DCM (0.5 mL), DMF (0.05 mL) and oxalyl chloride (0.070mL, 2.0 M in DCM) were added. The mixture was stirred for 3 min thencyclobutyl diazepine bis-HCl salt (27.6 mg, 0.122 mmol) and iPr₂NEt (0.1mL) were added to the reaction following dissolution in DCM (0.5 mL).The mixture was stirred for 3 min at 23° C. and was concentrated.Analysis by HPLC indicated a yield of 80%. Chromatography on SiO₂ gave21.5 mg (57%) of the title compound that was >90% pure by NMR.

Note: The synthesis may also be performed with ¹¹CO₂ to provide the¹¹C-labelled analog of the title compound.

Example 107(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate Step A:4-Cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester

A 3-L, 3-necked, round-bottomed flask under a positive pressure ofnitrogen was equipped with a mechanical stirrer and charged withtert-butylhomopiperazine-1-carboxylate (1-BOC-homopiperazine) (73.0 g,365.0 mmol) and anhydrous dichloroethane (800 mL). To this stirredsolution was added cyclobutanone (25.5 g, 363.8 mmol). The pale yellowreaction was stirred at rt for 1 h, following which, sodiumtriacetoxyborohydride (92.5 g, 436.3 mmol) was added portion-wise over 1h. The reaction mixture was stirred for 48 h. 1 N NaOH_((aq)) (225 mL)was added to the reaction mixture and stirred for 1 h. The phases wereseparated and the aqueous layer was extracted with dichloroethane (2×100mL). The organic layers were pooled, washed with satd. aq. NaCl (1×250mL), dried over anhydrous Na₂SO₄ and filtered. The solvent was removedby rotary evaporation under reduced pressure to afford the crude productas pale yellow semi-solid (92.4 g, 98%). ¹H-NMR (400 MHz, CDCl₃) δ ppm:3.59-3.40 (m, 4H), 2.98-2.84 (m, 1H), 2.59-2.43 (m, 4H), 2.12-2.03 (m,2H), 2.00-1.83 (m, 4H), 1.76-1.55 (m, 2H), 1.51-1.41 (s, 9H). MS m/z(ESI+): 255.2 (M+H⁺).

Step B: 1-Cyclobutyl-[1,4]diazepane dihydrochloride

A 1-L, 3-necked, round-bottomed flask was equipped with a mechanicalstirrer and a reflux condenser. The flask was charged with a slurry ofcrude 4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester(92.4 g, 363.8 mmol) in a mixture of dioxane/MeOH (100 mL/50 mL). HCl (4M in dioxane, 250 mL) was added with vigorous mechanical agitationfollowing which the reaction mixture was heated to ca. 55° C. in an oilbath. A pale orange-yellow solution resulted. The reaction mixture wasmaintained at ca. 55° C. for 16 h. After cooling to rt, the reactionmixture, a thick slurry, was transferred to a 2-L recovery flask andconcentrated to a pasty solid. Methyl tert-butyl ether (200 mL) wasadded, and the slurry agitated at ca. 55° C. in an oil bath for 1 h. Thesolvent was removed by rotary evaporation under reduced pressure toafford the product as an off-white solid (81.2 g, 98%). ¹H-NMR (400 MHz,DMSO-d₆) δ ppm: 11.92 (s, 1H), 9.87 (s, 1H), 9.46 (s, 1H), 3.76-3.03 (m,9H), 2.43-2.33 (m, 2H), 2.17-2.15 (m, 4H), 1.75-1.60 (m, 2H). MS m/z(ESI+): 155.1 (M+H⁺).

Step C:(6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

A 5-L, 3-necked, round-bottomed flask was equipped with a mechanicalstirrer and a thermocouple and charged with 1-cyclobutyl-[1,4]diazepanedihydrochloride (110.0 g, 484.6 mmol), 1 N NaOH (1400 mL) and isopropylacetate (600 mL). A pre-cooled (0° C.). solution of 6-chloronicotinylchloride (82.7 g, 470.0 mmol) in isopropyl acetate (800 mL) was addedvia an addition funnel at a rate such that the reaction temperature wasmaintained between 5-10° C. After the addition was complete, thereaction mixture was warmed to rt and stirred for 2 h (pH of reactionmixture ca. 5.6). The reaction mixture was basified with 2 N NaOH_((aq))(to pH ca. 13). The phases were separated and the aqueous layer wasextracted with isopropyl acetate (2×300 mL). Some reddish-brownflocculent material was observed during the extractions. The organiclayers were pooled and filtered through a pad of diatomaceous earth. Thefiltrate was washed with satd. aq. NaCl (1×300 mL) and dried overanhydrous Na₂SO₄. Filtration and removal of the solvent by rotaryevaporation under reduced pressure afforded the crude product as areddish brown oil (126.0 g, 91%). ¹H-NMR (400 MHz, CDCl₃) δ ppm: 8.45(m, 1H), 7.74 (m, 1H), 7.39 (m, 1H), 3.86-3.76 (m, 2H), 3.53-3.45 (m,2H), 3.05-2.80 (m, 1H), 2.70 (br s, 1H), 2.62-2.45 (m 3H), 2.10-1.56 (m,8H). MS m/z (ESI+): 294.1 (M+H⁺). HPLC (Method B): R=6.06 min.

Step D:(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

A 5-L, 3-necked, round-bottomed flask under a positive pressure ofnitrogen was equipped with a mechanical stirrer, thermocouple and areflux condenser. The flask was charged with anhydrous DMA (625 mL),4-fluorophenol (57.3 g, 511.6 mmol) and Cs₂CO₃ (278.0 g, 853.3 mmol).The yellow colored suspension was stirred for 15 min following which asolution of crude(6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone(125.0 g, 426.6 mmol) in anhydrous DMA (625 mL) was added via anaddition funnel over 0.5 h. The reaction mixture was heated to ca. 100°C. and maintained at that temperature for 12 h. The reaction mixture wascooled to rt, then filtered through a pad of diatomaceous earth (3″ padin a 600 mL coarse glass frit) and the pad was washed with DMA (2×125mL). The filtrate was diluted with ice water (ca. 1 L) and 2 NNaOH_((aq)) (500 mL). The pH of the reaction mixture was ca. 13. Out ofconvenience, the reaction mixture was divided into two approximatelyequal portions. Each portion was extracted with MTBE (3×300 mL). Theorganic layers were pooled, dried over anhydrous MgSO₄, filtered andconcentrated by rotary evaporation under reduced pressure to afford thea thick orange colored oil. HPLC analysis of the crude materialindicated a peak at ca. 9.18 min. The crude product was dissolved inanhydrous Et₂O (1 L) and stirred at rt for 16 h. A pale yellow solidprecipitated and this was collected by filtration (ca. 8.5 g). ¹H-NMR(D₂O) spectrum of this solid was very similar to that of the product.Upon stirring the solid in aq. HCl, the peak at 9.18 min slowlydisappeared with the concomitant appearance of a peak at 7.30 min(desired product). Presumably, the product formed a complex with thedrying agent (MgSO₄). Azeotropic drying or the use of sodium sulfate asthe drying agent is recommended. The solid was collected to give thetitle compound (120 g, 76% after Et₂O trituration). ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.23 (br s, 1H), 7.79 (dd, J=8.48, 2.39 Hz, 1H), 7.11-7.10(m, 4H), 6.95 (d, J=8.48 Hz, 1H), 3.76 (t, J=5.84 Hz, 2H), 3.55-3.50 (m,2H), 2.90-2.84 (m, 1H), 2.61 (t, J=4.71 Hz, 1H), 2.55-2.37 (m, 3H),2.06-1.92 (m, 3H), 1.88-1.56 (m, 5H). MS m/z (ESI+): 370.1 (M+H+). HPLC(Method B): R_(t)=7.30 min.

Step E:(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate

A 3-L, 3-necked, round-bottomed flask was equipped with a mechanicalstirrer, addition funnel and a thermocouple. The flask was charged witha solution of crude(4-cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone(118.0 g, 319.8 mmol) in ethanol/Et₂O (1:1, 800 mL). The reaction vesselwas cooled to ca. 5° C. in an ice-water bath. HCl (2 M in Et₂O, 152 mL,304 mmol, 0.95 equiv.) was added drop-wise via the addition funnel over30 min. The resulting suspension was stirred for 2 h, and then dilutedwith Et₂O (200 mL). The resulting suspension was stirred at rt for 16 h.The suspension was re-cooled to 0° C., maintained at that temperaturefor 2 h with agitation, then filtered. The filter-cake was broken andwashed with Et₂O/EtOH (60:40, 100 mL×3) and the product dried underhouse vacuum for 1 h, then in a vacuum oven at 50° C. for 48 h. Theproduct (113.5 g) was suspended in Et₂O (2 L) and agitated (mechanicalstirrer) for 6 h. The suspension was filtered, the filter-cake brokenand washed with Et₂O (3×100 mL). The product was dried in a vacuum ovenat 45° C. for 16 h (106.8 g, 82%). ¹H NMR (400 MHz, D₂O) δ ppm:8.09-8.05 (m, 1H), 7.88-7.81 (m, 1H), 7.13-7.09 (m, 4H), 7.02 (d, J=8.64Hz, 1H), 4.15-4.10 (m, 1H), 3.87-3.39 (m, 6H), 3.07-2.90 (m, 2H),2.28-1.99 (m, 6H), 1.75-1.63 (m, 2H). MS m/z (ESI+): 370.1 (M+H⁺). HPLC(Method B): R_(t)=7.13 min. Anal. calcd for C₂₁H₂₄FN₃O₂.HCl.H₂O(monohydrochloride-monohydrate): C, 59.50; H, 6.42; N, 9.91. Found: C,59.36; H, 6.66; N, 9.98.

Example 108(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate (Alternate Method) Step A: Ethyl6-(4-fluorophenoxy)nicotinate

To a 2-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer, a thermo couple, and a condenser was added DMF (194 mL), ethyl6-chloronicotinate (100.00 g, 0.522 mol), and 4-fluorophenol (65.09 g,0.575 mol). A brown solution formed after stirring for 5-10 min. To thesolution was then added Cs₂CO₃ (189.19 g, 0.575 mol) in one portion. Thereaction temperature increased from 20° C. to 30° C. over 10 min withoutexternal heating and then started cooling down. The resulting suspensionwas stirred at rt for 2-3 h and the internal reaction temperature cooledback to 23-25° C. The reaction mixture was then heated to 60° C. andstirred for 18-20 h. HPLC analysis indicated that the reaction wascomplete. The heating mantle was removed and the reaction mixture wasallowed to cool to 25-30° C. To the mixture was added deionized water(145.5 mL) in a steady stream over 5 min and a slight exotherm wasobserved. The resulting suspension was stirred at rt for 15-20 min. Twoadditional portions of deionized water (145.5 mL each) were added andthe suspension was stirred at rt for 15-30 min. The pH of the suspensionwas around 9-10. The solid product was collected by vacuum filtration,rinsed thoroughly with deionized water in portions. The filter cake asdried in a filter funnel by pulling through air for 24 h. The productwas isolated as a white solid (133.6 g). mp: 68.0° C. (by DSC). ¹H NMR(CDCl₃): δ 8.81 (d, J=2.6 Hz, 1H), 8.22 (dd, J=8.5, 2.6 Hz, 1H), 7.12(br s, 2H), 7.10 (d, J=1.0 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.38 (q,J=7.1 Hz, 2H), 4.38 (t, J=7.1 Hz, 3H). MS (ESI): M+H⁺=262.1.

Step B: [1,4]Diazepan-1-yl-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone

A 5-L, 4-necked round-bottomed flask fitted with an external coolingbath, overhead stirrer, thermometer, addition funnel, under a nitrogenatmosphere was charged with THF (2 L), a solution of homopiperazine(234.4 g, 2.34 mol) in THF (20 mL), and ethyl6-(4-fluorophenoxy)nicotinate (dry; 251.34 g, 0.962 mol). The mixturewas stirred to dissolve the solids, leaving a slightly cloudy solution.The mixture was cooled to ca. 0° C. and treated with hexyllithium(440.41 g, 1.43 mol) via an addition funnel over a period of ca. 0.75 to1 h. The addition rate and external cooling were adjusted such that theinternal reaction temperature was maintained between 0 and 10° C. Afteraddition of the hexyllithium is complete, the reaction was warmed to ca.25° C. and monitored by HPLC until the ester is consumed (ca. 2 h). Themixture was cooled to ca. 15° C. and quenched with water (1 L). Thephases were separated and the amount of product in the aqueous phase waschecked by HPLC prior to being discarded. The aqueous phase wasoptionally extracted with MTBE (¼ volume). The basic aqueous phase wasdiscarded and the combined organic phases were extracted with HCl (2 N,600 mL) (aqueous phase pH ca. 2-3). The phases were separated and theorganic phase was extracted with HCl (2 N, 200 mL). The organic phasewas discarded. The aqueous extracts were combined and allowed to standfor several hours for any remaining{4-[6-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-[1,4]diazepan-1-yl}-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone(diamide by-product) to crystallize as a fine solid. The solid wasremoved by filtration through a glass fiber filter and the filtrate wasextracted with MTBE (7×180 mL) to remove any remaining diamide. Theaqueous phase was treated with NaOH (50% w/w; 175.4 g, 2.19 mol). Oncethe pH was greater than 9, a second liquid phase separated. The twophases were separated and the aqueous phase was extracted with EtOAc(2×150 mL). The organic phases obtained from the basified aqueousextracts are combined and washed with satd. aq. NaCl (100 mL). Once thephases are completely separated, the organic phase was placed in adistillation apparatus and treated with EtOAc (100 mL). The excess EtOAcwas distilled at atmospheric pressure to azeotropically remove water. Anadditional charge of EtOAc (600 mL) was added in several portions anddistillation was continued (repeated until Karl-Fischer analysis of thepot residue showed less than 0.8% water). The residue was filtered hotto remove NaCl and the filtrate was stirred for several hours until alarge amount of solid formed. The mixture was treated slowly withheptane (500 mL) over a period of about 1 hour and allowed to stir anadditional hour. The solid is isolated by filtration and dried to givethe title compound (168.9 g). mp: 95.4° C. (by DSC). ¹H-NMR (CDCl₃): δ8.24 (d, J=2.2 Hz, 1H), 7.80 (dd, J=2.2, 8.4 Hz, 1H), 7.12 (s, 2H), 6.95(d, J=8.4 Hz, 1H), 3.76 (br m, 2H), 3.51 (br m, 2H), 3.60 (br m, 1H),2.90 (br m, 3H), 1.90 (br m, 1H), 1.80 (br s, 3H).

Step C:(4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanonehydrochloride monohydrate

To a 3-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer, a thermo couple, and a condenser was charged EtOAc (1080 mL)and (1,4-diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone(136.2 g, 0.428 mol). The resulting suspension was warmed to 32-35° C.to dissolve all solids. The solution was then cooled to 5-10° C.,treated with cyclobutanone (36.33 g, 0.513 mol), and the mixture wasstirred at 5-10° C. for 5-10 min. To the solution at 5-10° C. was addedsodium triacetoxyborohydride (143.09 g, 0.641 mol) in several portionsover 15-20 min. The reaction temperature was kept below 15° C. by usingcooling bath and by adjusting the addition rate. The resultingsuspension was stirred at 15° C. for 10-15 min and then at rt (20-24°C.) for 2.5-3 h. Once HPLC analysis indicated the reaction was complete(<1 area % starting material), the reaction was quenched with a solutionof K₂CO₃ (164.15 g, 1.175 mol) in deionized water (540 mL). The internalreaction temperature increased from 22° C. to 30° C. with a gentle gasevolution. The mixture was stirred for 20-30 min (pH ca. 10). Theorganic layer was separated and further washed with deionized water(3×540 mL). The organic layer was filtered through a pad of diatomaceousearth (10 g) and rinsed with EtOAc (270 mL). The combined organic layerwas assayed by HPLC (contained 143.88 g of free base, 90% crude yield).The solution was diluted with absolute EtOH (270 mL). To the solutionwas slowly added a solution of concentrated aqueous HCl (0.95 eq. of thefreebase based on HPLC assay; 36.73 g, 0.368 mol) in absolute ethanol(67 mL) and the resulting solution was stirred at rt (22-24° C.). After20-30 min, the mixture became cloudy and the product crystallizedslowly. After stirring at rt (22-24° C.) for 20-24 h, the solid productwas collected by vacuum filtration. The filter cake was rinsed withEtOAc (540 mL) in several portions, and air-dried for 30 min. The dampfilter cake was transferred to a glass dish and further dried in avacuum oven at 50° C. for 20-24 h. ¹H-NMR analysis of the solid productindicated the residual solvents were removed. The solid product was thenre-hydrated in a sealed oven at rt in the presence of a satd. solutionof ZnSO₄.7H₂O (100.0 g, 0.348 mol) in deionized water (200 mL) for 24-48h to form the monohydrate. The product was isolated as white solid(125.0 g). Karl-Fisher analysis: ˜4.25% water. mp: 143.4° C. (by DSCwith closed pan). ¹H NMR (d⁶-DMSO): δ 11.40 (br s, 1H), 8.26 (s, 1H),7.97 (br s, 1H), 7.24 (m, 4H), 7.11 (d, J=8.8 Hz, 1H), 4.12 (br m, 1H),3.64 (br m, 3H), 3.36 (br m, 3H), 2.98 (br m, 2H), 2.44 (br m, 3H), 2.13(br m, 3H), 1.66 (br m, 2H). MS (ESI): M+H⁺=370.2.

Biological Methods: H₃ Receptor Binding (Human)

Binding of compounds to the cloned human H₃ receptors, stably expressedin SK-N-MC cells, was performed as described by Barbier, A. J. et al.(Br. J. Pharmacol. 2004, 143(5), 649-661). Data for compounds tested inthis assay are presented in Table 1 as an average of the resultsobtained.

TABLE 1 Ex# Human H₃ K_(i) (nM) 1 29 2 56 3 66 4 56 5 71 6 32 7 57 8 689 11 10 10 11 7 12 5 13 6 14 2 15 8 16 2 17 5 18 2 19 4 20 1 21 2 22 18023 3 24 1 25 1 26 1 27 4 28 13 29 1 30 1 31 4 32 4 33 1 34 5 35 3 36 137 5 38 6 39 1 40 1 41 4 42 12 43 299 44 327 45 34 46 202 47 357 48 6749 115 50 18 51 2 52 4 53 49 54 104 55 21 56 5 57 3 58 10 59 3 60 29 616 62 36 63 32 64 165 65 2 66 1 67 2 68 2 69 2 70 2 71 2 72 2 73 4 74 775 9 76 19 77 22 78 24 79 10 80 253 81 3 82 1 83 1 84 2 85 1 86 1 87 9888 59 89 28 90 19 91 3 92 250 93 58 94 3 95 1 96 1 97 1 98 19 99 28 10098 101 59 102 1 103 1 104 2 105 11

H₃ Receptor Binding (Rat)

A rat brain without cerebellum (Zivic Laboratories Inc., Pittsburgh,Pa.) was homogenized in 50 mM Tris-HCl/5 mM EDTA and centrifuged at1,000 rpm for 5 min. The supernatant was removed and recentrifuged at15,000 rpm for 30 min. Pellets were rehomogenized in 50 mM Tris/5 mMEDTA (pH 7.4). Membranes were incubated with 0.8 nMN-[³H]-α-methylhistamine plus/minus test compounds for 60 min at 25° C.and harvested by rapid filtration over GF/C glass fiber filters(pretreated with 0.3% polyethylenimine) followed by four washes withbuffer. Nonspecific binding was defined in the presence of 100 μMhistamine. Inhibitory concentration (responsible for 50% inhibition ofmaximal effect, IC₅₀) values were determined by a single sitecurve-fitting program (GraphPad, San Diego, Calif.) and converted to K,values based on a N-[³H]-α-methylhistamine dissociation constant (K_(d))of 0.8 nM. Data for compounds tested in this assay are presented inTable 2 as an average of the results obtained.

TABLE 2 Rat H₃ Ex# K_(i) (nM) 9 130 11 447 12 51 13 54 14 10 18 68 19 6620 17 21 16 23 70 24 15 25 25 26 16 27 86 29 20 30 26 31 39 32 92 36 3037 130 39 21 40 36 41 75 51 60 52 110 56 179 57 132 84 37 102 17 105 32

Cyclic AMP Accumulation

Sublines of SK-N-MC cells were created that expressed a reporterconstruct and either the human or rat H₃ receptor. The pA₂ values wereobtained as described by Barbier et al. (2004). Data for compoundstested in these assays are presented in Table 3, as an average of theresults obtained (NT=not tested).

TABLE 3 Ex# Human pA₂ Rat pA₂ 9 8.06 7.35 11 8.53 NT 12 8.26 NT 14 9.268.16 19 9.38 8.48 24 9.15 8.36 25 9.22 8.42 26 9.64 8.67 29 9.09 8.45 309.27 8.38 31 8.62 8.12 39 9.40 8.38 40 8.88 7.87 51 8.64 7.66 56 8.637.86 59 8.51 7.57 61 8.44 7.49 65 8.94 9.18 66 8.95 7.94 67 8.87 8.17 688.61 7.80 70 8.72 7.72 73 9.51 8.92 74 8.05 7.44 83 9.48 8.49 86 9.488.50 95 9.48 8.50 97 9.48 8.49 102 9.70 8.92 104 9.14 8.37 NT = nottested

1. A compound of Formula (I):

wherein R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl; m is 1 or2; X is N or CH; Y is N or CR^(a); R^(a) is —H, —Z—Ar, —CH₂NR^(b)R^(c),—CN, —CO₂C₁₋₄alkyl, —CO₂H, or —CONR^(b)R^(c); where R^(b) and R^(c) areeach independently —H or —C₁₋₄alkyl; and R² is —H or —Z—Ar; with theproviso that one of X and Y is N and one of R^(a) and R² is —Z—Ar; whereZ is O or S; and Ar is a phenyl or monocyclic heteroaryl groupunsubstituted or substituted with one, two, or three R³ substituents;where each R³ substituent is independently selected from the groupconsisting of: halo, —C₁₋₄alkyl, —OH, —CN, —CONR^(d)R^(e), and —NO₂;where R^(d) and R^(e) are each independently —H or —C₁₋₄alkyl; or apharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,or a pharmaceutically active metabolite thereof.
 2. A compound asdefined in claim 1, wherein R¹ is methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, or tert-butyl.
 3. A compound as defined in claim 1,wherein R¹ is methyl or isopropyl.
 4. A compound as defined in claim 1,wherein R¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
 5. Acompound as defined in claim 1, wherein m is
 1. 6. A compound as definedin claim 1, wherein m is
 2. 7. A compound as defined in claim 1, whereinX is N, Y is CR^(a), and R² is —Z—Ar.
 8. A compound as defined in claim1, wherein X is CH, Y is N, and R² is —Z—Ar.
 9. A compound as defined inclaim 1, wherein X is N, Y is CR^(a), and R² is —H, where R^(a) is—Z—Ar.
 10. A compound as defined in claim 1, wherein R^(a) is —CN,—CONH₂, or —CH₂NH₂.
 11. A compound as defined in claim 1, wherein R^(a)is —H.
 12. A compound as defined in claim 1, wherein Z is O.
 13. Acompound as defined in claim 1, wherein Z is S.
 14. A compound asdefined in claim 1, wherein Ar is a phenyl, pyrrolyl, furanyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridyl, pyrimidinyl, or pyrazinyl group, each unsubstituted orsubstituted with one, two, or three R³ substituents.
 15. A compound asdefined in claim 1, wherein Ar is a phenyl group unsubstituted orsubstituted with one, two, or three R³ substituents.
 16. A compound asdefined in claim 1, wherein Ar is a 4-halophenyl group.
 17. A compoundas defined in claim 1, wherein Ar is phenyl, 3,4-dichlorophenyl,4-methylsulfanylphenyl, 3-chlorophenyl, 3-fluorophenyl,4-chloro-3-methylphenyl, 3-cyanophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 2-fluorophenyl, 3-chlorophenyl, 2,4-difluorophenyl,3,5-dichlorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,3-methyl-4-methylsulfanylphenyl, or 3-pyridyl.
 18. A compound of Formula(II):

wherein R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl; each R³substituent is independently selected from the group consisting of:halo, —C₁₋₄alkyl, —OH, —CN, —CONR^(d)R^(e), and —NO₂; where R^(d) andR^(e) are each independently —H or —C₁₋₄alkyl; and n is 0, 1, 2, or 3;or a pharmaceutically acceptable salt, a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof.
 19. A compoundas defined in claim 18, wherein R¹ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.
 20. A compound of Formula (III):

wherein R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl; each R³substituent is independently selected from the group consisting of:halo, —C₁₋₄alkyl, —OH, —CN, —CONR^(d)R^(e), and —NO₂; where R^(d) andR^(e) are each independently —H or —C₁₋₄alkyl; and n is 0, 1, 2, or 3;or a pharmaceutically acceptable salt, a pharmaceutically acceptableprodrug, or a pharmaceutically active metabolite thereof.
 21. A compoundas defined in claim 20, wherein R¹ is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. 22-25. (canceled)
 26. A method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by histamine H₃ receptor activity, comprisingadministering to the subject in need of such treatment an effectiveamount of a compound of Formula (I):

wherein R¹ is —C₁₋₄alkyl or saturated monocyclic cycloalkyl; m is 1 or2; X is N or CH; Y is N or CR^(a); R^(a) is —H, —Z—Ar, —CH₂NR^(b)R^(c),—CN, —CO₂C₁₋₄alkyl, —CO₂H, or —CONR^(b)R^(c); where R^(b) and R^(c) areeach independently —H or —C₁₋₄alkyl; and R² is —H or —Z—Ar; with theproviso that one of X and Y is N and one of R^(a) and R² is —Z—Ar; whereZ is O or S; and Ar is a phenyl or monocyclic heteroaryl groupunsubstituted or substituted with one, two, or three R³ substituents;where each R³ substituent is independently selected from the groupconsisting of: halo, —C₁₋₄alkyl, —OH, —CN, —CONR^(d)R^(e), and —NO₂;where R^(d) and R^(e) are each independently —H or —C₁₋₄alkyl; or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite thereof.
 27. The method accordingto claim 26, wherein the disease, disorder, or medical condition isselected from the group consisting of: cognitive disorders, sleepdisorders, psychiatric disorders, and other disorders.
 28. The methodaccording to claim 26, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: dementia,Alzheimer's disease, cognitive dysfunction, mild cognitive impairment,pre-dementia, attention deficit hyperactivity disorders,attention-deficit disorders, and learning and memory disorders.
 29. Themethod according to claim 26, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: learning impairment,memory impairment, and memory loss.
 30. The method according to claim26, wherein the disease, disorder, or medical condition is selected fromthe group consisting of: insomnia, disturbed sleep, narcolepsy with orwithout associated cataplexy, cataplexy, disorders of sleep/wakehomeostasis, idiopathic somnolence, excessive daytime sleepiness,circadian rhythm disorders, fatigue, lethargy, and jet lag.
 31. Themethod according to claim 26, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: sleep apnea,perimenopausal hormonal shifts, Parkinson's disease, multiple sclerosis,depression, chemotherapy, and shift work schedules.
 32. The methodaccording to claim 26, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: schizophrenia,bipolar disorders, manic disorders, depression, obsessive-compulsivedisorder, and post-traumatic stress disorder.
 33. The method accordingto claim 26, wherein the disease, disorder, or medical condition isselected from the group consisting of: motion sickness, vertigo,epilepsy, migraine, neurogenic inflammation, eating disorders, obesity,and substance abuse disorders.
 34. The method according to claim 26,wherein the disease, disorder, or medical condition is selected from thegroup consisting of: depression, disturbed sleep, fatigue, lethargy,cognitive impairment, memory impairment, memory loss, learningimpairment, attention-deficit disorders, and eating disorders.
 35. Acompound selected from the group consisting of:(4-Cyclobutyl-[1,4]diazepan-1-yl)-[5-(4-fluoro-phenylsulfanyl)-pyridin-2-yl]-methanone;[6-(4-Chloro-phenylsulfanyl)-pyridin-3-yl]-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone;(4-Cyclobutyl-[1,4]diazepan-1-yl)-(6-phenylsulfanyl-pyridin-3-yl)-methanone;(4-Cyclopentyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone;(4-Isopropyl-piperazin-1-yl)-[6-(3-methyl-4-methylsulfanyl-phenoxy)-pyridin-3-yl]-methanone;[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isopropyl-piperazin-1-yl)-methanone;(4-Ethyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone;(4-Cyclobutyl-[1,4]diazepan-1-yl)-(5-phenylsulfanyl-pyridin-2-yl)-methanone;[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-methyl-[1,4]diazepan-1-yl)-methanone;and[6-(4-Fluoro-phenoxy)-pyridin-3-yl]-(4-isobutyl-piperazin-1-yl)-methanone;and pharmaceutically acceptable salts thereof.
 36. (canceled)
 37. Themethod according to claim 26, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: age-relatedcognitive decline, REM-behavioral disorder, benign postural vertigo,tinitus, movement disorders, restless leg syndrome, eye-relateddisorders, macular degeneration, and retinitis pigmentosis. 38-66.(canceled)